Indoline derivatives

ABSTRACT

This invention relates to substituted indoline derivative compounds which are antagonists of the progesterone receptor, their preparation and pharmaceutical utility, particularly including contraception and treatment of benign or malignant neoplastic diseases, having the general structure:  
                 
 
     wherein R 1  and R 2  may be single substituents or fused to form spirocyclic rings.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of U.S. patent application Ser.No. 10/014,173, filed Dec. 11, 2001, which is a divisional of U.S.patent application Ser. No. 09/552,632, filed Apr. 19, 2000, now U.S.Pat. No. 6,391,807, which claims the benefit of the priority of U.S.patent application Ser. No. 60/183,058, filed May 4, 1999, nowabandoned.

BACKGROUND OF THE INVENTION

[0002] This invention relates to compounds which are antagonists of theprogesterone receptor, their preparation and utility.

[0003] Intracellular receptors (IR) form a class of structurally relatedgene regulators known as “ligand dependent transcription factors” (R. M.Evans, Science, 240, 889, 1988). The steroid receptor family is a subsetof the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

[0004] The natural hormone, or ligand, for the PR is the steroidprogesterone, but synthetic compounds, such as medroxyprogesteroneacetate or levonorgestrel, have been made which also serve as ligands.Once a ligand is present in the fluid surrounding a cell, it passesthrough the membrane via passive diffusion, and binds to the IR tocreate a receptor/ligand complex. This complex binds to specific genepromoters present in the cell's DNA. Once bound to the DNA the complexmodulates the production of mRNA and protein encoded by that gene.

[0005] A compound that binds to an IR and mimics the action of thenatural hormone is termed an agonist, whilst a compound which inhibitsthe effect of the hormone is an antagonist.

[0006] PR antagonists may used in contraception. In this context theymay be administered alone (Ulmann, et al, Ann. N.Y. Acad. Sci., 261,248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertilityand Sterility, 60, 610, 1993) or in combination with a partial ERantagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).

[0007] PR antagonists may also be useful for the treatment of hormonedependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub:Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovariancancers. PR antagonists may also be useful for the treatment ofnon-malignant chronic conditions such as fibroids (Murphy, et al, J.Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al,Fertility and Sterility, 56, 402, 1991).

[0008] PR antagonists may also be useful in hormone replacement therapyfor post menopausal patients in combination with a partial ER antagonistsuch as tamoxifen (U.S. Pat. No. 5,719,136).

[0009] PR antagonists, such as mifepristone and onapristone, have beenshown to be effective in a model of hormone dependent prostate cancer,which may indicate their utility in the treatment of this condition inmen (Michna, et al, Ann. N.Y. Acad Sci., 761, 224, 1995).

[0010] The compounds of this invention have been shown to act ascompetitive inhibitors of progesterone binding to the PR and act asantagonists in functional models, either/or in-vitro and in-vivo. Thesecompounds may be used for contraception, in the treatment of fibroids,endometriosis, breast, uterine, ovarian and prostate cancer, and postmenopausal hormone replacement therapy.

[0011] Described by Jones, et al, (U.S. Pat. No. 5,688,810) is the PRantagonist dihydroquinoline A.

[0012] Jones, et al, described the enol ether B (U.S. Pat. No.5,693,646) as a PR ligand.

[0013] Jones, et al, described compound C (U.S. Pat. No. 5,696,127) as aPR ligand.

[0014] Zhi, et al, described lactones D, E and F as PR antagonists (J.Med. Chem., 41, 291, 1998).

[0015] Zhi, et al, described the ether G as a PR antagonist (J. Med.Chem., 41, 291, 1998).

[0016] Combs, et al., disclosed the aride H as a ligand for the PR (J.Med. Chem., 38, 4880, 1995).

[0017] Perlman, et. al., described the vitamin D analog I as a PR ligand(Tet. Letters, 35, 2295, 1994).

[0018] Hamann, et al, described the PR antagonist J (Ann. N.Y. Acad.Sci., 761, 383, 1995).

[0019] Chen, et al, described the PR antagonist K (Chen, et al, POI-37,16^(th) Int. Cong. Het. Chem., Montana, 1997).

[0020] Kurihari, et. al., described the PR ligand L (J. Antibiotics, 50,360, 1997).

[0021] Kuhla, et al, disclosed the oxindole M as having cardiotonicactivity (WO 86/03749).

[0022] Weber, teaches the oxindole N for cardiovascular indications (WO91/06545).

[0023] Fischer, et al, describe a preparation for making compounds whichinclude the generic structure O (U.S. Pat. No. 5,453,516).

[0024] Singh, et al, described the PDE III inhibitor P (J. Med. Chem.,37, 248, 1994).

[0025] Andreani, et al, described the cytotoxic agent Q (Acta. Pharn.Nord., 2, 407, 1990).

[0026] Binder, et al, described structure R which is an intermediate forpreparing COX II inhibitors (WO 97/13767).

[0027] Walsh described the oxindole S as an intermediate (U.S. Pat. No.4,440,785, U.S. Pat. No. 4,670,566).

[0028] R₁═F, Cl, Br, alkyl, NH₂

[0029] R₂=alkyl, alkoxy, F, Cl, NH_(2,) CF₃

[0030] Bohm, et al, claim the oxindole T as cardiovascular agents (WO91/06545).

[0031] Bohm, et al, include the generic structure U (WO 91/04974).

[0032] JP 63112584 A contains the generic structure V:

[0033] Boar, et al, described the dioxolane W as an intermediate forpreparation of acetyl-cholinesterase inhibitors (WO 93/12085 A1).

[0034] Kende, et al, described methodology for preparing 3,3-substitutedoxindoles, e.g. X, that was utilized in the present invention (Synth.Commun., 12, 1, 1982).

DESCRIPTION OF THE INVENTION

[0035] This invention comprises compounds of the Formula 1:

[0036] wherein:

[0037] R₁ and R₂ are chosen independently from H, alkyl, substitutedalkyl; OH; O(alkyl); O(substituted alkyl); OAc; aryl; optionallysubstituted aryl; heteroaryl; optionally substituted heteroaryl;alkylaryl; alkylheteroaryl; 1-propynyl; or 3-propynyl;

[0038] or R₁ and R₂ are joined to form a ring comprising one of thefollowing:

[0039] —CH₂(CH₂)_(n)CH₂—; —CH₂CH₂CMe₂CH₂CH₂—; —O(CH₂)_(m)CH₂—;O(CH₂)_(p)O;

[0040] —CH₂CH₂OCH₂CH₂—; or —CH₂CH₂N(H or alkyl)CH₂CH₂—;

[0041] or R₁ and R₂ comprise a double bond to CMe₂, C(cycloalkyl), O, orC(cyloether);

[0042] n is an integer from 0 to 5;

[0043] m is an integer from 1 to 4;

[0044] p is an integer from 1 to 4;

[0045] R₃ is selected from H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ toC₆ alkyl, C₃ to C₆ alkenyl, alkynyl or substituted alkynyl, or COR^(A);

[0046] R^(A) is selected from H, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0047] R₄ is selected from H, halogen, CN, NH_(2,) C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, or substituted C₁ to C₆ aminoalkyl;

[0048] R⁵ is selected from the groups a), b) or c):

[0049] a) R⁵ is a trisubstituted benzene ring containing thesubstituents X, Y and Z as shown below:

[0050] wherein:

[0051] X is selected from the group of halogen, OH, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, S(O)alkyl,S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂,C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclic ring containing 1to 3 heteroatoms, COR^(B), OCOR^(B), or NR^(C)COR^(B);

[0052] R^(B) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0053] R^(C) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0054] Y and Z are independently selected from H, halogen, CN, NO₂, C₁to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ to C₃ thioalkyl; or

[0055] b) R⁵ is a five or six membered heterocyclic ring with 1, 2, or 3heteroatoms selected from O, S, SO, SO₂ or NR⁶ and containing one or twoindependent substituents from the group of H, halogen, CN, NO₂ and C₁ toC₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(D), orNR^(E)COR^(D);

[0056] R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0057] R^(E) is H, C1 to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0058] R⁶ is H, or C, to C₃ alkyl; or

[0059] c) R⁵ is an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety,the moiety being optionally substituted by from 1 to 3 substituentsselected from halogen, lower alkyl, CN, NO₂, lower alkoxy, or CF₃;

[0060] or a pharmaceutically acceptable salt thereof.

[0061] A preferred set of compounds of this invention is depicted bystructure 2, 2a:

[0062] wherein:

[0063] R⁵ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

[0064] X is taken from the group of halogen, CN, C₁ to C₃ alkoxy, C₁ toC₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining 1 to 3 heteroatoms or C₁ to C₃ thioalkoxy;

[0065] Y is a substituent on the 4′ or 5′ position of the disubstitutedbenzene ring selected from the group of H, halogen, CN, NO₂, C₁ to C₃alkoxy, C₁ to C₄ alkyl, or C₁ to C₃ thioalkyl;

[0066] or a pharmaceutically acceptable salt thereof.

[0067] Another preferred group of this invention comprises compounds offormulas 2 and 2a wherein R⁵ is a five membered ring with the structureshown below:

[0068] U is O, S, or NR⁶,

[0069] R⁶ is H, or C₁ to C₃ alkyl, C₁ to C₄ CO₂alkyl,

[0070] X′ is selected from the group of halogen, CN, NO₂, C₁ to C₃ alkylor C₁ to C₃ alkoxy; with a proviso that, when X′ is CN, U is not NR⁶;

[0071] Y′ is selected from H, F, CN, NO₂ or C₁ to C₄ alkyl;

[0072] or a pharmaceutically acceptable salt thereof.

[0073] Another preferred group of formulas 2 and 2a are those in whichR⁵ is a six membered ring with the structure shown

[0074] wherein:

[0075] X¹ is N or CX²,

[0076] X² is halogen, CN or NO₂;

[0077] or pharmaceutically acceptable salt thereof.

[0078] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in Formula1 and 2 the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

[0079] The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having 1 to 8carbon atoms; “alkenyl” is intended to include both straight- andbranched-chain alkyl groups with 1 or 2 carbon-carbon double bonds andcontaining 2 to 8 carbon atoms; “alkynyl” group is intended to coverboth straight- and branched-chain alkyl groups with at least 1 or 2carbon-carbon triple bonds and containing 2 to 8 carbon atoms.

[0080] The terms “substituted alkyl”, “substituted alkenyl”, and“substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as justdescribed having one or more substituents from the group includinghalogen, CN, OH, NO₂, amino, aryl, heterocyclic, substituted aryl,substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy,alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio. Thesesubstituents may be attached to any carbon of an alkyl, alkenyl, oralkynyl group provided that the attachment constitutes a stable chemicalmoiety.

[0081] The term “aryl” is used herein to refers to an aromatic systemwhich may be a single ring or multiple aromatic rings fused or linkedtogether as such that at least one part of the fused or linked ringsforms the conjugated aromatic system. The aryl groups include, but arenot limited to, phenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl,and phenanthryl.

[0082] The term “substituted aryl” refers to aryl as just defined having1 to 4 substituents from the group including halogen, CN, OH, NO₂,amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substitutedalkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

[0083] The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, but are not limited to, tetrahydrofuran, piperidinyl,piperazinyl, 2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl,pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isooxazolyl,morpholinyl, indolyl, quinolinyl, thienyl, furyl, benzofuranyl,benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, andisoquinolinyl.

[0084] The term “substituted heterocyclic” is used herein to describethe heterocyclic just defined having 1 to 4 substituents selected fromthe group which includes halogen, CN, OH, NO₂, amino, alkyl, substitutedalkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy,aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino,or arylthio.

[0085] The term “thioalkyl” is used herein to refer to the SR group,where R is alkyl or substituted alkyl, containing 1 to 8 carbon atoms,preferably 1 to 6 carbon atoms. The term “alkoxy” is used herein torefer to the OR group, where R is alkyl or substituted alkyl, containing1 to 8 carbon atoms, preferably 1 to 6 carbon atoms. The term “aryloxy”is used herein to refer to the OR group, where R is aryl or substitutedaryl, as defined above. The term “alkylcarbonyl” is used herein to referto the RCO group, where R is alkyl or substituted alkyl, containing 1 to8 carbon atoms, preferably 1 to 6 carbon atoms. The term “alkylcarboxy”is used herein to refer to the COOR group, where R is alkyl orsubstituted alkyl, containing 1 to 8 carbon atoms, preferably 1 to 6carbon atoms. The term “aminoalkyl” refers to both secondary andtertiary amines wherein the alkyl or substituted alkyl groups,containing 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, whichmay be either the same or different and the point of attachment is onthe nitrogen atom. The term “halogen” refers to Cl, Br, F, or I.

[0086] The compounds of this invention may be prepared according to themethods described below.

[0087] According to scheme 1, commercially available oxindole 5 istreated with a mixture of a strong organo-metallic base (e.g. butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide) in aninert solvent (e.g. THF, diethyl ether) under nitrogen at reducetemperature (ca. −20° C.) (Kende, et al, Synth. Commun., 12, 1, 1982).The resulting di-anion is then treated with excess electrophile such asan alkyl halide, preferably the iodide. If R₁ and R₂ are to be joinedsuch as the product 6 contains a spirocycle at position 3, then theelectrophile should be bifunctional, i.e. a diiodide. Subsequentbromination of 6 proceeds smoothly with bromine in acetic acid (anorganic co-solvent such as dichloromethane may be added as required) inthe presence of sodium acetate, to afford the aryl bromide 7. Thebromide 7 is reacted with a palladium salt (e.g.tetrakis(triphenylphoshine)palladium(0)), in a suitable solvent (e.g.THF, dimethoxyethane, ethanol, toluene) at room temperature under aninert atmosphere (argon, nitrogen). The mixture is then treated with anarylboronic acid or boronic acid ester and a base (sodium carbonate,triethylamine, potassium phosphate) in water or fluoride source (cesiumfluoride) under anhydrous conditions. The required product 8 is thenisolated and purified by standard means.

[0088] If R₁ and R₂ are different, then the intermediate 6 is preparedby reacting the dianion of 5 with one equivalent of the electrophileR₁×X (X=leaving group e.g. I). The resultant mono-alkylated compound maybe then isolated and re-subjected to the reaction conditions using R₂—X,or alternatively used in-situ for the second alkylation with R₂—X.Alternatively if the desired product 8 is to contain R₂═H, then theisolated mono-alkylated intermediate is taken though the subsequentsteps.

[0089] Other methodologies are also available for coupling the pendantaryl group, Ar, to the oxindole platform, for example reaction ofcompound 7 with an aryl stannane, aryl zinc, or aryl magnesium halide inthe presence of a palladium or nickel catalyst (scheme 2). The requiredaryl-metallic species described above are formed through standardtechniques.

[0090] Other functionalities can easily be installed into the 3-positionof the indoline platform according to scheme 3. Oxidation of theunsubstituted indoline 9, preferably under neutral or acidic conditions(e.g. selenium dioxide in dry dioxane at reflux) affords the isatin 10.Compound 10 may be further functionalized to provide a ketal 11 bytreatment with an alcohol and acid catalyst under dehydratingconditions. Alternatively reaction of 10 with a second ketone undersuitable conditions (piperidine in toluene at reflux; or TiCl₄/Zn in THFat reflux) affords alkylidene derivatives 12. Reaction of the isatin 10with a grignard reagent or organolithium affords tertiary alcohols 13(R═H). These alcohols may then be further functionalized by alkylationor acylation procedures.

[0091] Treatment of the bromide 7 in an anhydrous solvent (e.g. THF,Et₂O) with a strong base (sodium hydride preferred, sodiumhexamethyldisilazide, potassium hydride) followed by reaction at reducedtemperature (−50 to −20° C.) with n-butyllithium andN,N,N,N′-tetramethylethylenediamine followed after a suitable period oftime by a trialkylborate (tri methyl or triisopropylborate) gives afteracidic work-up the boronic acid 14 (scheme 4). Compound 14 may then bereacted under palladium catalyzed conditionstetrakis(triphenylphosphine)palladium(0), base (NaHCO₃, Na₂CO₃, K₂CO₃,triethylamine, CsF) solvent (toluene/EtOH/water, THF/water,dimethoxyethane/water, anhydrous dimethoxyethane) with an aryl bromide,aryl iodide, aryltrifluoromethane sulfonate of aryl fluorosulfonate, toprovide the desired compounds 8.

[0092] An alternative strategy would be to prepare an organo zinc ormagnesium reagent from compound 7 and react it in-situ with an arylbromide, aryl iodide, aryltrifluoromethane sulfonate ofarylfluorosulfonate, under palladium catalyzed conditions to affordcompound 8. Such an organo zinc or magnesium species could be preparedby treatment of the bromide 7 in an anhydrous solvent (e.g. THF, Et₂O)with a strong base (sodium hydride preferred, sodiumhexamethyldisilazide, potassium hydride) followed by reaction at reducedtemperature (−50 to −20° C.) with n-butyllithium andN,N,N′,N′-tetramethylethylenediamine followed after a suitable period oftime by reaction with anhydrous zinc chloride or magnesium bromide.

[0093] The compounds of the present invention can be used in the form ofsalts derived from pharmaceutically or physiologically acceptable acidsor bases. These salts include, but are not limited to, the followingsalts with inorganic acids such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid and, as the case may be, such organic acidsas acetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

[0094] This invention includes pharmaceutical compositions andtreatments which comprise administering to a mammal a pharmaceuticallyeffective amount of one or more compounds as described above asantagonists of the progesterone receptor.

[0095] The progesterone receptor antagonists of this invention, usedalone or in combination, can be utilized in methods of contraception andthe treatment and/or prevention of benign and malignant neoplasticdisease. Specific uses of the compounds and pharmaceutical compositionsof invention include the treatment and/or prevention of uterinemyometrial fibroids, endometriosis, benign prostatic hypertrophy;carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon,prostate, pituitary, meningioma and other hormone-dependent tumors.Additional uses of the present progesterone receptor antagonists includethe synchronization of the estrus in livestock.

[0096] When the compounds are employed for the above utilities, they maybe combined with one or more pharmaceutically acceptable carriers orexcipients, for example, solvents, diluents and the like, and may beadministered orally in such forms as tablets, capsules, dispersiblepowders, granules, or suspensions containing, for example, from about0.05 to 5% of suspending agent, syrups containing, for example, fromabout 10 to 50% of sugar, and elixirs containing, for example, fromabout 20 to 50% ethanol, and the like, or parenterally in the form ofsterile injectable solutions or suspensions containing from about 0.05to 5% suspending agent in an isotonic medium. Such pharmaceuticalpreparations may contain, for example, from about 25 to about 90% of theactive ingredient in combination with the carrier, more usually betweenabout 5% and 60% by weight.

[0097] The effective dosage of active ingredient employed may varydepending on the particular compound employed, the mode ofadministration and the severity of the condition being treated. However,in general, satisfactory results are obtained when the compounds of theinvention are administered at a daily dosage of from about 0.5 to about500 mg/kg of animal body weight, preferably given in divided doses twoto four times a day, or in a sustained release form. For most largemammals, the total daily dosage is from about 1 to 100 mg, preferablyfrom about 2 to 80 mg. Dosage forms suitable for internal use comprisefrom about 0.5 to 500 mg of the active compound in intimate admixturewith a solid or liquid pharmaceutically acceptable carrier. This dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

[0098] These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvents customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

[0099] The preferred pharmaceutical compositions from the standpoint ofease of preparation and administration are solid compositions,particularly tablets and hard-filled or liquid-filled capsules. Oraladministration of the compounds is preferred.

[0100] These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0101] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

[0102] The present invention may be further understood by the followingnon-limiting examples.

EXAMPLE 1

[0103] 5-(3-Nitro-penal)-1,3-dihydro-indol-2-one

[0104] 5-(Bromo)-1,3-dihydro-indol-2-one.

[0105] A solution of oxindole (2.0 g, 15.0 mmol) and sodium acetate (2.1g, 25.5 mmol) in CHCl₃ (20 cm³) was treated with bromine (2.4 g, 15.0mmol) in CHCl₃ (10 cm³). After 30 min. the mixture was allowed to warmto RT and stirred for 1 h. The reaction mixture was diluted with EtOAc(500 cm³) and poured into water. The aqueous layer was extracted withEtOAc (×2), the combined organic layers were washed with water, sat.sodium hydrogen carbonate solution, brine, dried (MgSO₄), and evaporatedto give the title compound (3.1 g, 14.6 mmol, 96%) as an off-white solidwhich was used without further purification: m.p. 221-223° C.; ¹H NMR(DMSO-d₆) δ3.51 (s, 2H), 6.76 (d, 1H, J=8.1 Hz), 7.33(dd, 1H, J=8.1, 1.7Hz), 7.37 (s, 1H), 10.49 (br s, 1H); ¹³C NMR (DMSO-d₆) δ36.10 (t),111.21 (d), 113.16 (s), 127.54 (d), 128.3 (s), 130.40 (d), 143.34 (s),176.24 (s); MS (El) m/z 211, 213 (M)⁺.

[0106] 5-bromo-2-indolinone (1.08 g, 5.09 mmol) and tetrakistriphenylphosphine Pd (0) (0.273 g) were stirred under an atmosphere of nitrogenin ethylene glycol dimethyl ether (35 mL). After 15 minutes,3-nitrophenyl boronic acid (1.70 g, 10.2 mmol) was added, followed bypotassium carbonate (4.24 g, 30.7 mmol) in water (15 mL). The reactionwas heated to reflux overnight, cooled to room temperature and thenfiltered. Saturated ammonium chloride was added. The water layer wasextracted with ethyl acetate (3×20 mL). The combined organic layer wasdried with MgSO₄, filtered, and solvent removed in vacuo. The productwas purified by flash silica gel chromatography (3:2 hexane; ethylacetate) to give 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one (0.084 g,65%), Mp=269° C.; ¹H NMR (DMSO) δ10.5 (s, 1 H), 8.38−8.36 (m, 1 H)8.17−8.14 (m, 1 H), 8.10−8.07 (m, 1 H), 7.75−7.60 (m, 3 H), 6.95 (d, 1H, J=8.1 Hz), 3.57 (s, 2 H); IR (KBr) 3420, 3190, 1700 cm⁻¹; MS (EI) m/z253 (M−H)⁻; CHN calculated for C₁₄H₁₀N₂O: C, 66.14; H, 3.96; N, 11.02;Found: C, 64.59; H, 4.16; N, 9.43.

EXAMPLE 2

[0107] 3-methyl-5-(3-nitrophenyl)-1,3-dihydroindol-2-one

[0108] 5-bromo-3-methyl-indol-2-one

[0109] Under an atmosphere of nitrogen, bromine (0.96 g, 6.0 mmol) inacetic acid (5 cm³) was added drop wise to a solution of3-methyl-2-indolinone (0.8749 g, 6.0 mmol) (Kende, et al, Synth.Commun., 12, 1, 1982) and sodium acetate (0.50 g, 6.0 mmol) in aceticacid (10 cm³). The reaction was stirred at room temperature for 3.5 h.Saturated sodium carbonate was added to quench the reaction. The waterlayer was extracted with EtOAc (×3), dried (MgSO₄), filtered, andevaporated to give the title compound (1.26 g, 93%), Mp=119-120° C.; ¹HNMR (DMSO) δ1.32 (d, 3 H, J=7.66 Hz), 3.45 (q, 1 H, J=7.62 Hz), 6.77 (d,1 H, J=8.23 Hz), 7.46 (s, 1 H), 7.36−7.33 (m, 1 H), 10.4 (s, 1 H); IR(KBr) 3200, 1725 cm⁻¹; MS (EI) m/z 224/226 (M−H)⁻; CHN calculated forC₉H₈BrNO: C, 47.82; H, 3.57; N, 6.20; Found: C, 47.44; H, 3.42; N, 6.04.

[0110] 5-Bromo-3-methyl-1,3-dihydro-indol-2-one (0.50 g, 2.22 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.15 g) were stirred under anatmosphere of nitrogen in dimethoxyethane (18 cm³). After 15 min.,3-nitrophenyl boronic acid (0.74 g, 4.45 mmol) was added, followed bypotassium carbonate (1.86 g, 13.5 mmol) in water (7 cm³). The reactionwas heated to reflux for 8 h and then stirred at room temperatureovernight. Saturated ammonium chloride was added; and the aqueous layerwas extracted with EtOAc (×3). The combined organic layers were dried(MgSO₄), filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc: hexane 1:2); eluted: 2:1 hexane; ethylacetate, to give the title compound (0.30 g, 47%), mp 200-203° C.; ¹HNMR (DMSO-d₆) δ1.41 (d, 3 H, J=7.61 Hz), 3.50 (q, 1 H, J=7.60 Hz), 6.96(d, 1 H, J=8.08 Hz), 7.62 (d, 1 H, J=8.06 Hz), 7.75−7.70 (m, 2 H),8.18−8.10 (m, 2 H), 8.41−8.39 (m, 1 H), 10.5 (s, 1 H); IR (KBr) 3450,1700 cm⁻¹; MS (EI) m/z 267 (M−H); Anal. Calc. for C₁₅H₁₂N₂O₃+0.2C₄H₈O₂:C, 66.61; H, 4.46; N, 9.83; Found: C, 66.26; H, 4.59; N, 10.06.

EXAMPLE 3

[0111] 5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

[0112] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one

[0113] 3,3-dimethyl-indol-2-one (0.65 g, 4.03 mmol) and sodium acetate(0.33 g, 4.07 mmol) were stirred in acetic acid (5 cm³) then bromine(0.66 g, 4.13 mmol) in acetic acid (5 cm³) was added drop-wise to thereaction mixture. The reaction was stirred for 50 min., and then pouredinto water. The mixture was basified with sodium carbonate and thenextracted with ethyl acetate (×3), dried (MgSO₄), filtered, andevaporated to the title compound (0.89 g, 92%) ¹H NMR (DMSO-d₆) δ1.21(s, 6 H), 6.76 (d, 1 H, J=8.22 Hz), 7.29 (dd, 1 H, J=2.12 Hz, 8.23 Hz),7.49 (d, 1 H, J=2.03 Hz), 10.4 (s, 1H).

[0114] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.33 g, 1.38mmol) and tetrakis(triphenylphosphine)palladium(0) (0.094 g) werestirred under an atmosphere of nitrogen in dimethoxyethane (12 cm³).After 15 minutes, 3-methoxyphenylboronic acid (0.42 g, 2.76 mmol) wasadded, followed by potassium carbonate (1.15 g, 8.34 mmol) in water (5cm³). The reaction was heated to reflux for 5 hours, and then cooled toroom temperature. Saturated aqueous ammonium chloride and EtOAc wereadded and the mixture was filtered. The aqueous layer was extracted withEtOAc (×2), and the combined organic layers were dried (MgSO₄),filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc: hexane 1:3) to afford the title compound(0.11 g, 31%), mp=157-158° C.; ¹H NMR (DMSO-d₆) δ3.34 (s, 6 H), 3.82 (s,3 H), 6.87-6.93 (m, 2 H), 7.20−7.15 (m, 2 H), 7.37−7.32 (m, 1 H),7.49−7.46 (m, 1 H), 7.63 (d, 1H, J=1.14 Hz), 10.4 (s, 1 H); MS (EI) m/z266 (M−H)⁻; Anal. Calc. for C₁₇H₁₇NO₂: C, 76.38; H, 6.41; N, 5.24;Found: C, 76.02; H, 6.49; N, 5.02.

EXAMPLE 4

[0115] 5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

[0116] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (0.98 g, 4.07mol) and, tetrakis(triphenylphosphine)palladium(0) (0.239 g) werestirred under an atmosphere of nitrogen in dimethoxyethane (35 cm³).After 15 min., 3-chlorophenylboronic acid (1.27 g, 8.13 mol) was added,followed by potassium carbonate (3.40 g, 45 mmol) in water (15 cm³). Thereaction was heated to reflux for 2 hours and then stirred at roomtemperature overnight. The mixture was diluted with sat. ammoniumchloride and extracted with EtOAc (×3). The combined organic layers weredried (MgSO4), filtered, and evaporated. The residue was purified bycolumn chromatography (SiO₂, EtOAc: hexane, 1:3) to afford the titlecompound (0.284 g, 25%): mp 188-189° C.; ¹H NMR (DMSO-d₆) δ3.34 (s, 6H), 6.93 (d, 1 H, J=8.04 Hz), 7.38−7.35 (m, 1 H), 7.53−7.43 (m, 2 H),7.61 (d, 1 H, J=7.68 Hz), 7.70 (s, 2 H), 10.40 (s, 1 H); IR (KBr) 3420,3150, 3050, 1700 cm⁻¹; MS (EI) m/z 270 (M−H)⁻; Anal. Calc. forC₁₆H₁₄ClNO+0.1C₄H₈O₂: C, 70.21; H, 5.32; N, 4.99; Found: C, 70.3; H,5.44; N, 4.93.

EXAMPLE 5

[0117] 3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one

[0118] 5-bromo-1,3-dihydro-3,3-dimethyl-2H-indol-2-one (1.02 g, 4.26mmol) and tetrakis(triphenylphosphine)palladium(0) (0.244 g) werestirred under an atmosphere of nitrogen in dimethoxyethane (35 cm³).After 15 minutes, 3-nitrophenylboronic acid (1.43 g, 2.56 mmol) wasadded, followed by potassium carbonate (3.54 g, 2.56 mmol) in water (15cm³). The reaction was heated to reflux for 2 hours and then stirred atroom temperature overnight. Saturated ammonium chloride and EtOAc wereadded and the mixture was filtered. The aqueous layer was extracted withethyl acetate (×2), and then the combined organic layers were dried(Na₂SO₄), filtered, and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc: hexane, gradient elution) to afford thetitle compound (0.86 g, 67%) mp 234-235° C.; ¹H NMR (DMSO-d₆) δ3.33 (s,6 H), 6.98 (d, 1 H, J=8.06 Hz), 7.61 (dd, 1H, J=1.85, 8.03 Hz), 7.73 (t,1 H, J=7.98 Hz), 7.81 (d, 1 H, J=1.63 Hz), 8.11-8.18 (m, 2 H), 8.42-8.43(m, 1H), 10.5 (s, 1 H); MS (EI) m/z 281; Anal. Calc. forC₁₆H₁₄N₂O₃.0.2H₂O: C, 67.51; H, 4.92; N, 9.37; Found: C, 67.48; H, 5.17;N, 9.48.

EXAMPLE 6

[0119] 5-(3-Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one

[0120] 3-Ethyl-indol-2-one

[0121] A solution of oxindole (40 g, 0.3 mol) in dry THF (400 ml) underN₂ was cooled to −25° C. and treated drop wise with n-butyl lithium(2.5M in hexanes, 240 ml, 0.6 mol). To the resulting solution was addedN,N,N′,N′-tetramethylethylenediamine (90.4 ml, 0.6 mol). After 30 min.iodoethane (48 ml, 0.6 mol) was added and the reaction mixture wasallowed to warm to RT and stirred over night. The reaction mixture waspoured into aqueous NH₄Cl solution, extracted with EtOAc (2×) and thecombined organic layers were washed with dil. HCl, water, brine, dried(MgSO₄) and concentrated. The residual oil was triturated with hexane toafford the crude product (24.5 g, 51%). A sample (3 g) wasrecrystallized from EtOAc/hexane to obtain the title compound (1.4 g),m.p. 100-101° C; ¹H-NMR (DMSO-d₆) δ0.76 (t, 3H, J=7.5 Hz), 1.8-2.0 (m,2H), 3.38 (t, 3H, J=5.7 Hz), 6.8 (dt, 1H, J=7.69, 0.45 Hz), 6.93 (dt,1H, J=7.45, 1.10 Hz), 7.15 (m, 1H), 7.22 (m, 1 H), 10.3 (s, 1H); MS(ESI) m/z 270 [M+H].

[0122] 5-Bromo-3-ethyloxindole

[0123] A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate(4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g,40 mmol). After 30 min. the mixture was diluted with water and extractedwith EtOAc (2×); the combined organic layers were washed with water,sat. sodium hydrogen carbonate solution, and brine, dried (MgSO₄) andevaporated to afford the crude product (9.2 g, 96%). A sample wasrecrystallized from EtOAc/hexane to obtain the subtitled compound, m.p.130-132° C.; ¹H-NMR (DMSO-d₆) δ0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H),3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43(s, 1H); MS (−ESI) m/z 238/240 (M−H).

[0124] A solution of 5-bromo-3-ethyl-oxindole (3.5 g, 14.6 mmol),3-chlorophenylboronic acid (2.4 g, 15 mmol), potassium carbonate (4.5 g,33 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.87 g, 0.75mmol) in dimethoxyethane (160 ml), ethanol (40 ml), and water (40 ml)was heated to reflux to 6 hours. After cooling to RT, the mixture wasdiluted with water and extracted with EtOAc (3×). The combined organicextracts were washed with water, then brine, dried (MgSO₄) andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc:hexane 1:3) to afford the title compound (0.46 g, 12%), m.p.118-120° C.; ¹H-NMR (DMSO-d₆) δ0.78 (t, 3H, J=7.25 Hz) 1.8-2.02 (m, 2H),3.47 (t, 1H, J=5.71 Hz), 6.89 (d, 3H, J=8.1 Hz), 7.35 (m, 1H), 7.44 (t,1H, J=7.91 Hz), 7.51 (m, 1H), 7.58 (m, 2H), 7.67 (t, 1H, J=1.76 Hz),10.5 (s, 1H); MS (−ESI) m/z 270 (M−H).

EXAMPLE 7

[0125] 5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one

[0126] A solution of 3-ethylindol-2-one (16 g, 0.1 mol) in dry THF (200ml) under N₂ was cooled to −25° C. and treated drop wise withn-butyllithium (2.5M in hexanes, 80 ml, 0.2 mol). To the resultingsolution was added N,N,N′,N′-tetramethylethylenediamine (30 ml, 0.2mol). After 30 min. iodoethane (8 ml, 0.1 mol) was added and thereaction mixture was allowed to warm to RT and stirred over night. Thereaction mixture was poured into an aqueous NH₄CT solution, extractedwith EtOAc (2×) and the combined organic layers were washed with dil.HCl, water, brine, dried (MgSO₄) and concentrated. The residual oil wastriturated with hexane to afford the title product (9 g, 45%), m.p.156-159° C.; ¹H NMR (DMSO-d,) δ10.44 (s, 1H), 7.70−7.69 (t, 1H),7.62−7.59 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.53−7.50 (m, 1H), 7.45−7.41(t, 1H), 7.36−7.35 (m, 1H), 7.34−7.33 (m, 1H), 6.91−6.89 (d, 1H J=8.2Hz), 1.87−1.80 (m, 2H), 1.77−1.70 (m, 2H), 0.54−0.50 (t, 6H); MS (+ESI)m/z 190 (M+H).

[0127] 5-Bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one

[0128] A solution of 3,3-diethylindol-2-one (8 g, 40 mmol) and sodiumacetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine(6.4 g, 40 mmol). After 30 min. the mixture was diluted with water andextracted with EtOAc (2×); the combined organic layers were washed withwater, sat. sodium hydrogen carbonate solution, then brine, dried(MgSO₄) and evaporated to afford the crude product (7.6 g, 75%). Asample was recrystallized from EtOAc/hexane to obtain the subtitledcompound, m.p. 164-165° C.; ¹H-NMR (DMSO-d₆) δ10.45 (s, 1H), 7.41−7.40(d, 1H, J=2.2 Hz), 7.34−7.31 (m, 1H), 6.78−6.76 (d, 1H J=8.2 Hz),1.78−1.65 (m, 4H), 0.50−0.46 (m, 6H); MS (−ESI) m/z 266/268 (M−H).

[0129] A solution of 5-bromo-1,3-dihydro-3,3-diethyl-[2H]-indol-2-one(2.7 g, 10 mmol), 3-chlorophenylboronic acid (1.6 g, 10 mmol), potassiumcarbonate (4 g, 30 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.5 g, 0.4 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), andwater (25 ml) was heated to reflux for 6 hours. After cooling to RT, themixture was diluted with water and extracted with EtOAc (2×). Thecombined organic extracts were washed with water, then brine, dried(MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:hexane 1:3) to afford the title compound(0.8 g, 27%), m.p. 195-197° C.; ¹H-NMR (DMSO-d₆) δ7.70 (t, 1 H, J=2 Hz),7.62−7.60 (m, 1H), 7.58 (d, 1H, J=1.7 Hz), 7.52, (dd, 1H, J=8.1, 2 Hz),7.43 (t, 1H, J=7.9 Hz), 7.36−7.33 (m, 1H), 6.90 (d, 1H, J=8.1 Hz),1.87−1.70 (m, 4H) and 0.52 (t, 6H, J=7.4 Hz); MS (+APCI) m/z 300/302(M−H).

EXAMPLE 8

[0130] 5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one

[0131] A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm³)under N₂ was cooled to 0° C. and treated drop-wise with methyl magnesiumbromide (3M in diethylether, 14.7 cm³, 44 mmol) and the mixture wasallowed to warm up-to room temperature. The reaction was poured intosat. ammonium chloride solution, then extracted into EtOAc (×3). Thecombined organic layers were then washed with water, brine, dried(MgSO₄) and evaporated. The residue was then purified by columnchromatography (SiO₂, EtOAc: hexane, gradient elution) to afford5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol,29%): ¹H NMR (DMSO-d₆) δ1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)⁻.

[0132] 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.0 g, 4.1mmol) was dissolved in dry DMF (15 cm³) cooled to 0° C. and treated withpotassium tert-butoxide (1M in THF, 4.5 cm³, 4.5 mmol). After 15 min.methyl-p-toluenesulfonate (0.93 g, 5 mmol) was added and the mixture wasallowed to warm up-to room temperature. After 2 h the mixture was pouredinto saturated ammonium chloride solution and extracted with EtOAc (×2),then the combined organic layers were washed with water, sodiumhydroxide (1N, ×2), water (×3), dried (MgSO₄) and evaporated. Theresidue was then purified by column chromatography (SiO₂, EtOAc: hexane,gradient elution) to afford5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.56 g, 2.2 mmol,53%): ¹H NMR (CDCl₃) δ1.59 (s, 3H), 3.18 (s, 3H), 6.73 (d, 1H, J=8.2Hz), 7.45 (dd, 1H, J=8.2, 2 Hz), 7.52 (d, 1H, J=2 Hz); MS (EI) m/z 225(M)⁺.

[0133] A solution of 5-bromo-3-methoxy-3-methyl-1,3-dihydro-indol-2-one(0.52 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g,0.1 mmol) was dissolved in dimethoxyethane (22 cm³). After 15 min.,3-chlorophenylboronic acid (0.63 g, 4.1 mmol) and sodium carbonate (1.0g) in water (10 cm³) was added and the reaction was heated under reflux.After 2 h the mixture was cooled, poured into water and extracted withEtOAc (×2), the combined organic extracts were washed with sodiumhydroxide solution (1N, ×2) water, brine, dried (MgSO₄) and evaporated.The residue was then purified by column chromatography (SiO₂, EtOAc:hexane, 5:1) to afford5-(3-chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one (0.17 g,0.58 mmol, 29%): ¹H NMR (CDCl₃) δ1.65 (s, 3H), 2.91 (s, 1H), 3.24 (s,3H), 6.92 (d, 1H, J=8.1 Hz), 7.26-7.38 (m, 2H), 7.43-7.46 (m, 1H),7.52-7.55 (m, 1H), 7.62 (d, 1H, J=1.8 Hz); MS ((+) APCI) m/z 288 (M+H)⁺.

EXAMPLE 9

[0134]5-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one

[0135] To a solution of 5-bromoisatin (2.5 g, 11 mmol) in dry THF (100cm³) at −10° C. under a nitrogen atmosphere was added1-propynylmagnesium bromide (0.5 M in THF, 47 cm³, 23.5 mmol). After 1h, the mixture was poured into saturated ammonium chloride and extractedwith EtOAc (×3), washed with brine, dried (MgSO₄) and evaporated toafford 5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (2.83 g,10.6 mmol, 97%) which was used without further purification: (CDCl₃)δ1.83 (s, 3H), 6.79 (d, 1H, J=8.0 Hz), 6.90 (s, 1H), 7.41-7.44 (m, 2H),10.59 (s, 1H); MS ((−) ESI) m/z 264 (M−H)⁻.

[0136] To a solution of5-bromo-3-hydroxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (1.0 g, 3.75mmol) in dry DMF (15 cm³) at 0° C., was added potassium tert-butoxide(1M in THF, 4.1 cm³, 4.1 mmol). After 15 min. methyl p-toluenesulfonate(0.85 g, 4.6 mmol) was added and the mixture was allowed to warm up toroom temperature. After 16 h the mixture was poured into saturatedammonium chloride, extracted with EtOAc (×3), washed with water, brine,dried (MgSO₄) and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc: hexane 1:3) to afford5-bromo-3-methoxy-3-prop-1-1-ynyl-1,3-dihydroindol-2-one (0.62 g, 2.21mmol, 59%): (CDCl₃) δ inter alia 1.87 (s, 3H), 3.19 (s, 3H), 3.35 (s,1H), 6.72 (d, 1H, J=8.3 Hz), 7.48 (dd, 1H, J=8.3, 2 Hz), 7.63 (d, 1H,J=2 Hz): MS (EI) m/z 279 (M)⁺.

[0137] 5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g,2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10mmol) were stirred at room temperature in dimethoxyethane (22 cm³).After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodiumcarbonate (1.06 g, 10 mmol) in water (11 cm³) were added and the mixtureheated under reflux. After 16 h, the mixture was cooled, poured intowater and extracted with EtOAc (×3). The combined organic layers werewashed with sodium hydroxide (1N, ×2), brine, dried (MgSO₄) andevaporated. The residue was subjected to column chromatography (SiO₂,EtOAc: hexane, gradient elution) and the product triturated with hexaneto afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid:mp.>190° C. (decomp.); (CDCl₃) δ1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s,1H), 6.91 (d, 1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H),7.54-7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).

EXAMPLE 10

[0138] 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one

[0139] A solution of the 5-bromoxindole (0.5 g, 2.4 mmol) andtetrakis(triphenylphosphine) palladium (0.14 g, 0.12 mmol) indimethoxyethane (10 cm³) was stirred under N₂ for 20 min. To thismixture was then added 3-chlorophenylboronic acid (0.44 g, 2.83 mmol)and sodium carbonate (0.75 g, 7.1 mmol) in water (4 cm³). The solutionwas brought to reflux for 6 h then cooled to RT, poured into water andextracted with EtOAc (×3). The combined organic extracts were washedwith water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate: hexane 1:3) toafford the title compound (0.49 g, 2.0 mmol, 86%) as a tan solid: m.p.169-171 ° C., ¹H NMR (THF-d₈) δ3.45 (s, 2H), 6.85 (d, 1H J=8.1 Hz), 7.25(d, J=8.0 Hz, 1H), 7.35 (dd, J=7.8, 7.8Hz, 1H), 7.43 (d, J=8.1 Hz, 1H),7.49 (d, J=7.8Hz, 1H), 7.50 (s, 1H), 7.59 (dd, J=1.78, 1.78 Hz, 1H), 9.5(br s, 1H); ¹³C NMR (THF-d₈) δ36.39 (t), 109.80, 123.97, 125.55, 127.19(d), 127.68 (s), 130.89 (d), 133.73, 135.29, 144.23, 145.09, 176.45 (s);MS (EI) m/z 243, 245 (M)⁺; Anal. (C₁₄H₁₀ClNO) C, H, N.

EXAMPLE 11

[0140]5′-(3-Chlorophenyl)spirol[1,3-dioxolane-2,3′-[3H]indol]-2′(1′H)-one

[0141] 5-[3-Chloro-phenyl]-1H-indole-2,3-dione

[0142] A solution of 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one (10.0g, 41 mmol) in dioxane (200 cm³) and SeO₂ (22.8 g, 205 mmol) was broughtto reflux for 2 h then cooled to RT and concentrated onto Florisil. TheFlorisil was washed (acetone:CHCl₃ 1:9) and the combined organicextracts were evaporated. The residue was purified by columnchromatography (SiO₂, acetone:CHCl₃ 1:8) to afford the subtitledcompound (8 g, 31 mmol, 76%) as a tan solid: m.p. 256-258° C., ¹H NMR(TUF-d₈) δ6.96 (d, J=8.8 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.4 (dd,J=7.7, 7.7 Hz, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.68 (dd, J=1.84, 1.84 Hz,1H), 7.83-7.86 (m, 2H), 10.05 (br s, 1H); ¹³C NMR (DMSO-d₆) δ113.30 (d),119.08 (s), 123.44, 125.57, 126.65, 127.92, 131.41 (d), 133.88, 134.47(s), 137.25 (d), 141.51, 150.99, 160.15, 184.83 (s); MS (EI) m/z 256(M−H)⁺; Anal. (C₁₄H₈ClNO₂−0.1 H₂O) C, H, N.

[0143] A solution of the 5-[3-chloro-phenyl]-1H-indole-2,3-dione (0.5 g,1.9 mmol) in toluene (30 cm³) and ethylene glycol (1.1 cm³, 19.4 mmol)and pTsOH (0.04 g, 0.2 mmol) was brought to reflux with azeotropicremoval of water for 12 h then cooled to RT. The reaction mixture wasdiluted with EtOAc (100 cm³) and washed with water, sat. sodium hydrogencarbonate solution, brine, dried (MgSO₄), and evaporated to give an oilyresidue. The residue was purified by column chromatography (SiO₂,CH₂Cl₂) to afford the title compound (0.47 g, 1.6 mmol, 80%) as a tansolid: m.p. 159-161° C. ; ¹H NMR (DMSO-d₆) δ4.29-4.39 (M, 4H), 6.93 (d,J=8.6 Hz, 1H), 7.4 (d, J=8.1 Hz, 1H), 7.46 (dd, J=7.9, 7.9 Hz, 1H), 7.7(d, J=7.7 Hz, 1H), 7.68-7.71 (m, 3H), 10.55 (s, 1H); ¹³C NMR (DMSO-d₆)δ65.53 (t), 110.89, 123.25, 124.81 (d), 125.65 (s), 125.83, 126.79,130.09, 130.61 (d), 132.96, 133.64, 141.53, 14267, 174.36 (s); MS (EI)m/z 301/303 (M)⁺; Anal. (C₁₆H₁₂ClNO₃) C, H, N.

EXAMPLE 12

[0144] 5′-(3-Chlorophenyl)spiro[1,3-dioxane-2,3′-[3H]indol]-2′(1′H)-one

[0145] The title compound was prepared according to the procedure forexample 11: m.p. 242-244° C.; ¹H NMR (DMSO-d6) δ1.7 (M, 1H), 2.2 (M,1H), 3.95 (m, 2H), 4.78 (t, 2H), 6.9 (d, J=7.9 Hz, 1H), 7.39 (d, J=7.9Hz, 1H), 7.46 (dd, J=7.9, 7,9 Hz, 1H), 7.59-7.68 (m, 3H), 10.59 (br s,1H); ¹³C NMR (DMSO-d₆) 6 25.19, 60.68 (t), 93.58 (s), 110.94, 122.93,125.29, 126.29, 127.19 (d), 128.65 (s), 129.92, 131.07 (d), 133.16,134.08, 141.61, 142.15, 173.29 (s); MS (EI) m/z 315/317 (M)⁺; Anal.(C₁₇H₁₄ClNO₃) C, H, N.

EXAMPLE 13

[0146] 5′-(3-nitrophenyl)spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0147] Spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0148] To a −25° C. solution of oxindole (2.0 g, 15.0 mmol) in 40 (cm³)of anhydrous THF under N₂ was added n-butyllithium (1.6 M in hexanes,19.7 cm³, 31.5 mmol) drop-wise. To the resulting milky solution wasadded N,N,N′,N′-tetramethylethylenediamine (4.75 cm³, 31.5 mmol). After30 min. a solution of 1,4-diiodobutane (21.9 g, 70.6 mmol) in THF (3cm³) was added and the reaction mixture was allowed to warm to RT andstirred for 14 h. The reaction mixture was poured into water, extractedwith EtOAc (×2), then the combined organic layers were washed with dil.HCl (pH 1), water (×2), dried (MgSO₄) and evaporated. The residue waspurified by column chromatography (SiO₂, EtOAc: hexane 1:4) to affordthe subtitled compound (1.4 g, 7.5 mmol, 50%) as a tan solid: ¹H NMR(CDCl₃) δ1.8-2.2 (m, 8H), 6.94 (dd, J=7.5, 1.0 Hz, 1H), 7.01 (dd, J=7.5,1.0 Hz, 1H), 7.14-7.25 (m, 2H), 9.30 (br s, 1H).

[0149] 5-Bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0150] A solution of spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one(0.27 g, 1.4 mmol) and sodium acetate (0.12 g, 1.46 mmol) in acetic acid(10 cm³) was treated with bromine (0.24 g, 1.51 mmol) in acetic acid (2cm³). After 30 min. the mixture was poured into sat. sodium hydrogencarbonate solution and extracted with EtOAc (×2), the combined organiclayers were washed with water, sat. sodium hydrogen carbonate solution,water, dried (MgSO₄), and evaporated to give the subtitled compound(0.37 g, 1.47 mmol, 96%) as an off-white solid which was used withoutfurther purification: ¹H NMR (CDCl₃) δ1.8-2.27 (m, 8H), 6.79 (d, J=8 Hz,1H), 7.30-7.39 (m, 2H), 8.63 (br s, 1H).

[0151] A solution of5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (0.3 g, 1.1 mmol)and tetrakis(triphenylphosphine)palladium(0) (0.07 g, 0.06 mmol) indimethoxyethane (8 cm³) was stirred under N₂ for 20 min. To this mixturewas then added 3-nitrophenylboronic acid (0.23 g, 1.4 mmol) and sodiumcarbonate (0.36 g, 3.4 mmol) in water (3 cm³). The solution was broughtto reflux for 3 h then cooled to RT, poured into water and extractedwith EtOAc (×3). The combined organic extracts were washed with water,brine, dried (MgSO₄), and evaporated. The residue was purified by columnchromatography (SiO₂, ethyl acetate: hexane 1:3) to afford the titlecompound (0.21 g, 0.68 mmol, 62%) as a yellow solid: m.p. 238-240° C; ¹HNMR (DMSO-d₆) δ1.89-1.99 (m, 8H), 6.96 (d, J=8.1 Hz, 1H), 7.58 (dd,J=8.1, 1.8 Hz, 1H), 7.66 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.0, 8.0 Hz,1H), 8.13 (dd, J=7.0, 1.0 Hz, 2H), 8.4 (d, J=1.8 Hz, 1H), 10.42 (br s,1H); ¹³C NMR (dioxane-d₈) δ26.31, 38.13 (t), 53.85 (s), 108.9, 121.15,121.33, 126.23, 129.38, 132.11 (d), 132.6, 138.32, 141.84, 142.74,149.14, 182.68 (s); MS (EI) m/z 308 (M)⁺.

EXAMPLE 14

[0152] 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde

[0153] Spiro[cyclohexane-1,3′-[3H]indol]-2′-(1′H)one

[0154] A solution of oxindole (25 g, 0.19 mol) in anhydroustetrahydrofuran (800 cm³) was cooled to −20° C., then n-butyllithium(2.5M in hexanes, 152 cm³, 0.38 mol) was added slowly followed byN,N,N′,N′-tetramethylethylenediamine (51 cm³, 0.38 mol,). After 15 min.1,5-diiodopentane (174 g, 0.54 mol) was added slowly and the mixture wasallowed to warm to room temperature. After stirring for 16 h. saturatedaqueous ammonium chloride solution (1L) and EtOAc (1L) were added. After15 min. the layers were separated and the aqueous phase was extractedEtOAc (×2). The combined organic layers were extracted with hydrochloricacid (1N), then washed with brine (500 cm³), dried (MgSO₄), andconcentrated to obtain an oil. The oil was triturated with hexane (200cm³) and benzene (20 cm³). The precipitate was collected and dried invacuo to obtain the subtitled compound (26.3 g, 69.6%) as colorlesscrystals: mp 110-114° C.; ¹H NMR (DMSO-d₆) δ1.67 (m, 10H), 6.84 (d, 1H,J=8 Hz) 6.94 (t, 1H, J=8 Hz), 7.17 (t, 1H, J=8 Hz), 7.44 (d, 1H, J=8Hz), 10.3 (s, 1H).

[0155] 5′-Bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0156] To a solution of spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(17.6 g, 0.09 mol) in acetic acid (300 cm³) was added sodium acetate(8.0 g, 0.1 mol) and bromine (14.6 g, 0.091 mol) with stirring. After 30min. at room temperature, the reaction mixture was partitioned betweenwater and EtOAc. The aqueous phase was extracted twice with EtOAc. Thecombined organic layers were washed with water, dried (MgSO₄) andevaporated and the residue was triturated with hexane. The precipitatewas collected, and dried in vacuo to obtain the subtitled compound (16.5g, 67%) as off-white crystals: mp 196-199° C.; ¹H NMR (DMSO-d₆) δ1.62(m, 10H), 6.8 (d, 1H, J=6.8 Hz), 7.36 (d, 1H, J=8.2, 1.8 Hz), 7.58 (dd,1H, J=8.2, 1.8 Hz), 10.44 (s, 1H).

[0157] To a solution of5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.00 g, 3.57mmol) in dimethoxyethane (20 cm³) was addedtetrakis(triphenylphosphine)palladium (0.20 g, 0.17 mmol) undernitrogen. After 15 min. 3-formylphenylboronic acid (1.00 g, 6.93 g) wasadded followed by potassium carbonate (2.90 g, 21 mmol) in water (10cm³). After 20 h at reflux, the mixture was cooled, poured into waterand extracted with EtOAc (×3). The combined organic extract was washedwith sat. brine, dried (MgSO₄) and evaporated. The residue was purifiedby column chromatography (SiO₂, EtOAc: hexane, gradient elution) toafford the title compound (0.66 g, 2.15 mmol, 60%) as a white solid, ¹HNMR (CDCl₃) δ1.65-1.85 (m, 6H), 1.86-2.08 (m, 4H), 7.22 (d, 1H, J=8 Hz),7.48 (dd, 1H, J=8, 2 Hz), 7.61 (t, 1H, J=8 Hz), 7.66 (d, 1H, J=2 Hz),7.81-7.88 (m, 2H), 8.06 (t, 1H, J=2 Hz), 8.30 (s, 1H, br); MS ((+)ESI)m/z 306 (M+H)⁺.

EXAMPLE 15

[0158] 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime

[0159] To a solution of3-(1′,2′-dihydro-2′-oxospirocyclohexane-1,3′-[3H]indol-5′-yl)benzaldehyde (0.59 g, 1.95 mmol) in EtOH: H₂O (10 cm³, 8:2) was addedhydroxylamine hydrochloride (0.17 g, 2.5 mmol) and sodium acetate (0.20g, 2.5 mmol). After 20 min. the mixture was concentrated, water wasadded, and extracted with EtOAc (×2). The combined organic layers werewashed with sat. sodium hydrogen carbonate solution, water, sat. brine,dried (MgSO₄) and evaporated to afford the title oxime (0.63 g, 1.95mmol, 100%) which was used without further purification, ¹H NMR (CDCl₃)δ1.60-1.84 (m, 6H), 1.85-2.00 (m, 4H), 6.86 (d, 1H, J=8 Hz), 7.36 (dd,1H, J=8, 2 Hz), 7.43-7.50 (m, 1H), 7.57-7.67 (m, 2H), 7.85 (s, 1H, br),8.25 (s, 1H), 8.68 (s, 1H, br), 8.94 (s, 1H, br); MS ((−)ESI) m/z 319(M−H)³¹ .

EXAMPLE 16

[0160] 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde methyloxime ether

[0161] To a solution of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde (0.24 g, 0.79 mmol), and sodium acetate (0.083 g, 1.00mmol) in EtOH: water (5 cm³, 8:2) was added methoxylamine hydrochloride(0.083 g, 1.00 mmol). After 30 min. the precipitate was isolated byfiltration and washed with EtOH: water (8:2, ×2), to afford the titlecompound (0.027 g, 0.08 mmol, 10%) as a white solid: mp 198-200(decomp.) ¹H-NMR: 1.58-2.07 (m, 10H), 4.00 (s, 3H), 6.98 (d, 1H, J=8Hz), 7.42-7.49 (m, 2H), 7.53-7.58 (m, 2H), 7.64 (d, 1H, J=7.75 (s, 1H),8.07 (s, 1H, br), 8.15 (s, 1H); MS ((+)−ESI) m/z 335 (M+H)⁺.

EXAMPLE 17

[0162]5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-pyridinecarbonitrile

[0163] A solution of 3-bromopyridine-5-carbonitrile (2.79 g, 15.26mmol), hexamethylditin (5.00 g, 15.26 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol) inanhydrous dimethoxyethane (30 cm³) under N₂ was heated under reflux.After 16 h the mixture was concentrated and purified by columnchromatography (SiO₂, EtOAc: hexane 5:95) to afford3-cyanopyridine-5-trimethylstannane (2.82 g, 10.55 mmol, 69%): ¹H NMR(CDCl₃) δ0.40 (s, 9H), 8.01 (m, 1H), 8.80 (m, 2H); MS ((+) APCI) m/z 269(M+H)⁺.

[0164] A solution of5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (1.97 g, 7.05mmol), 3-cyanopyridine-5-trimethylstannane (2.26 g, 8.46 mmol),bis(triphenylphosphine)palladium(II)chloride (0.33 g, 0.47 mmol) andlithium chloride (1.48 g, 35 mmol) in anhydrous toluene (30 cm³) washeated under reflux. After 16 h the mixture was cooled, partitionedbetween EtOAc and water, the aqueous layer was re-extracted with EtOAc(×2), the combined organic extracts were washed with water, dried(MgSO₄) and evaporated. The residue was subjected to columnchromatography (SiO₂, EtOAc: hexane, 1:2) and then further purified bypreparative LC (Primesphere C18, 10 micron, 50×250 mm, MeCN: H₂O 1:1,100 cm³/min., RT 7.92 min.) to afford the title compound as whitecrystals (0.56 g, 1.84 mmol, 26%): mp. 232-234° C., ¹H NMR (CDCl₃)δ1.68-1.89 (m, 6H), 1.93-2.13 (m, 4H), 7.12 (d, 1H, J=8 Hz),7.49 (dd,1H, J=8.2 Hz), 7.66 (d, 1H, J=2 Hz), 8.15 (t, 1H, J=2 Hz), 8.39 (s, 1H,br), 8.89 (d, 1H, J=2 Hz), 9.06 (d, 1H, J=2 Hz); MS ((+)−ESI) m/z 304(M+H)⁺.

EXAMPLE 18

[0165] 5′-(Pyrimidin-5-yl)-spiro[cyclohexane]-1,3′-[3H]indol]-2′(1H)-one

[0166] To a solution of 5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′-(1H)-one (11 g, 0.04 mol) in drytetrahydrofuran (200 cm³) was added sodium hydride (60% dispersion inmineral oil, 1.6 g, 0.04 mol). After 30 min. stirring at roomtemperature, the mixture was cooled to −78° C. and butyl lithium (1.7Min hexanes, 23.2 cm³, 0.04 mol) was added slowly. After 30 min.di-iso-propylborate (25 cm³, 0.11 mol) was added and the mixture wasallowed to warm to room temperature. After 2 hrs. hydrochloric acid (1N,500 cm³) and ethylacetate (500 cm³) were added. The aqueous phase wasextracted with ethylacetate, then the combined organic layers werewashed with water, brine, dried (MgSO₄) and evaporated. The residue wastriturated with hexane and the precipitate dried in vacuo to obtain(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid(8.3 g, 86%) as an off-white solid that was used without furtherpurification. A sample that was further triturated with ethyl acetatehad the following properties: mp. 255-260° C. dec.; ¹H NMR (DMSO-d₆)δ1.50 (m, 2H), 1.73 (m, 8H), 6.82 (d, 1H, J=7.72 Hz) 7.66 (d, 1H, J=7.72Hz) 7.91 (s, 3H, br), 10.36 (s, 1H); MS ((−)ESI) m/z 244 [M−H].

[0167] A stirred mixture of 5-bromopyrimidine (3.2 g, 20 mmol) intoluene (20 cm³),2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl) boronic acid(0.49 g, 2.2 mmol) in ethanol (10 cm³), potassium carbonate (0.28 g, 2.0mmol) in water (10 cm³) and tetrakis (triphenylphosphine)palladium (0)(0.15 g, 0.13 mol) was heated overnight under reflux and in anatmosphere of nitrogen. The reaction mixture was treated with 20 mL ofsodium bicarbonate solution and was then extracted with ethyl acetate(2×50 mL). The combined organic phases were washed with saturated brine,dried (MgSO₄). Recrystallization from ethanol gave 0.13 g of pureproduct, mp 227-228° C. IR (KBr) 1700 cm⁻¹ ¹H-NMR (DMSO-d₆) δ10.48 (s,1H), 9.13 (s,1H), 9.11 (s,2H), 7.86 (s, 1H) 7.63 (dd, 1H; J=1.5 Hz and8.1 Hz), 6.98 (d, 1H J=8.1 Hz), 6.98 (d, 1H, J=8.1 Hz) 1.75 (m, 10); MS(ESI) m/z 278 (M−H).

EXAMPLE 19

[0168] 5-(3-chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0169] Prepared according to the procedure for example 14: mp. 164-165°C., ¹H NMR (CDCl₃) δ1.60-1.78 (m, 6H), 1.81-1.99 (m, 4H), 7.04 (d, J=8.1Hz, 1H) 7.22-7.47 (m, 4H), 7.53 (s, 1H), 7.61 (s, 1H), 9.28 (br s, 1H);¹³C-NMR (CDCl₃) δ20.17, 24.12, 31.92 (t), 47.22 (s), 109.21, 121.94,124.06, 125.50, 125.79, 125.97, 126.38, 128.96 (d), 132.88, 133.59,135.60, 139.14, 142.17, 182.89 (s); MS (EI) m/z 310, 312 (M−H)⁺.

EXAMPLE 20

[0170]5′-(3-Chloro-4-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0171] Prepared according to the procedure for example 18: mp 188-189°C.; ¹H-NMR (CDCl₃) δ7.97 (s, 1H), 7.57−7.54 (m, 2H), 7.41−7.34 (m, 2H),7.20 (t, 1H, J=8.7 Hz), 9.96 (d, 1H, J=8.1 Hz), 2.04−1.65 (m, 10H); MS((+)APCI) m/z 330 [M+H]⁺.

EXAMPLE 21

[0172] 5-(3-Fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0173] Prepared according to the procedure for example 18: mp 171-172°C.; ¹H-NMR (CDCl₃) δ8.43 (s, 1H), 7.62 (d, 1H, J=1.8 Hz), 7.42 (dt, 1H,J=6.2, 2.0 Hz), 7.39−7.37 (m, 1H), 7.33 (dt, 1H, J=5.1, 1.3Hz), 7.26(dq, 1H, J=5.9, 2.1 Hz), 7.05−6.99 (m, 2H), 2.03−1.64 (m, 10H); MS((+)APCI) m/z 296 [M+H]⁺.

EXAMPLE 22

[0174]5′-(3,5-Difluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0175] Prepared according to the procedure for example 18: mp 180-183°C.; ¹H-NMR (CDCl₃) δ8.35 (s, 1H), 7.59 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H,J=6.2, 2.0 Hz), 7.10−7.03 (m, 2H), 6.99 (d, 1H, J=8.1 Hz), 7.76 (tt, 1H, J=4.3, 2.3 Hz), 2.05−1.62 (m, 10H); MS ((+)APCI) m/z 314 [M+H]⁺.

EXAMPLE 23

[0176] 5-(3,4-Difluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0177] Prepared according to the procedure for example 14: m.p. 187-189°C.; ¹H-NMR (DMSO-d₆) δ1.5-2.0 (m, 10H), 6.9 (d, J=8.13 Hz, 1H),7.40-7.51 (m, 3H), 7.66-7.76 (m, 2H), 10.4 (s, 1H); MS (−ESI) m/z 312(M−H)⁻.

EXAMPLE 24

[0178] 5-[3-(Methylthio)phenylspiro[cyclo-hexane-1,3-[3]indol]-2(1H)-one

[0179] Prepared according to the procedure for example 18: ¹H NMR(CDCl₃) δ1.62-2.06 (m, 10H), 2.54 (s, 3H), 6.96 (d, J=8.0 Hz, 1H),7.2-7.5 (m, 5H), 7.6 (s, 1H), 7.75 (s, 1H); ¹³C NMR (DMSO-d₆) δ16.37(q), 21.62, 25.58, 33.37 (t), 48.67 (s), 110.55, 123.56, 124.36, 125.68,126.94, 129.64 (d), 135.31, 136.91, 139.33, 140.27, 142.49, 184.29 (s);MS (EI) m/z 324 (M+H)⁺.

EXAMPLE 25

[0180]5′-[3-(Methysulfinylphenyl]spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0181] A solution of5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]indol]-2(1H)-one(0.15 g, 0.46 mmol) in methanol (6 cm³) was treated with NaIO₄ (0.11 g,0.51 mmol). The reaction was allowed to stir at RT overnight. Themethanol was evaporated and the residue taken up in EtOAc (50 cm³) andH₂O. The EtOAc layer was washed with brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,CH₂Cl₂:methanol, 8:2) to afford the title compound (0.11 g, 0.32 mmol,70%) as a white solid: m.p. 190-191° C. ¹H NMR (CDCl₃) δ1.65-2.05 (m,10H), 2.80 (s, 3H), 7.02 (dd, J=8.0, 3.1 Hz, 1H), 7.46 (d, J=8.0 Hz,1H), 7.52-7.75 (m, 4H), 7.0 (s, 1H), 8.7 (s, ¹H); ¹³C NMR (DMSO-d₆)δ21.59, 25.54, 33.44 (t), 44.38 (q), 48.46 (s), 110.53, 12.05, 123.31,127.08, 129.94, 130.15 (d), 134.17, 137.2, 140.73, 143.27, 146.61,183.71 (s); MS (EI) m/z 339 (M)⁺.

EXAMPLE 26

[0182]5-[3-(Methysulfonyl)phenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0183] A solution of the5-[3-(Methylthio)phenyl]spiro[cyclo-hexane-1,3-[3H]-indol]-2(1H)-one(0.15 g, 0.46 mmol) in CH₂Cl₂ (2 cm³) was added to a solution of mCPBA(0.4 g, 2.3 mmol) in CH₂Cl₂ (5 cm³) at RT. The reaction was allowed tostir overnight. The mixture was diluted with CH₂Cl₂ (50 cm³) and washedwith saturated bicarbonate solution, water, brine, dried (MgSO₄), andevaporated. The residue was crystallized (Hexane-EtOAc) to afford thetitle compound (0.132 g, 0.8 mmol, 80%) as an off white solid: m.p. 240°C.; ¹H NMR (CDCl₃) δ1.55-2.1 (m, 10H), 3.15 (s, 3H), 7.01 (d, J=8.1 Hz,1H), 7.47 (dd, J=8.1, 1.5 Hz, 1H), 7.6-7.7 (m, 2H), 7.82-7.97 (m, 3H),8.12 (s, 1H); ¹³C NMR (DMSO-d₆) δ21.54, 25.50, 33.45 (t), 44.97 (q),48.44 (s), 110.60, 123.28, 125.92, 127.20, 128.52, 130.31 (d), 132.46,133.65, 137.34, 140.70, 141.53, 143.25, 183.63 (s); MS (EI) m/z 356(M+H)⁺.

EXAMPLE 27

[0184]5′-(3-Chloro-5-fluorophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0185] Prepared according to the procedure for example 18: mp 178-180°C.; ¹H—NMR (CDCl₃) δ8.50 (s, 1H), 7.57 (d, 1H, J=1.8 Hz), 7.39 (dd, ¹H,J=6.2, 1.9 Hz), 7.33−7.32 (m, 1H), 7.15 (dq, 1H, J=5.7, 1.7, 0.7 Hz),7.06 (dq, 1 H, J=4.2, 1.9, 0.4 Hz), 7.00 (d, 1H, J=8.1 Hz), 2.05−1.64(m, 10H); MS ((−)ESI) [M−H]⁻@m/z 328.

EXAMPLE 28

[0186]5-(3-Bromo-5-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0187] Prepared according to the procedure for example 18: mp. 194-196°C.; ¹H NMR (CDCl₃) δ1.66-2.04 (m, 10H), 7.00 (d, 1H, J=8.0 Hz),7.17-7.28 (m, 2H), 7.41 (dd, 1H, J=8, 1.8 Hz), 7.49 (t, 1H, J=1.4 Hz),7.58 (d, 1H, J=1.5 Hz) 8.24 (s, 1H, br); MS ((+)−EI) m/z 373/375 [M⁺].

EXAMPLE 29

[0188]5′-(3-Fluoro-5-methylphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0189] A solution of 3-fluoro-5-methoxybenzene trifluoromethanesulfonate(1.6 g, 5.8 mmol) and tetrakis-(triphenylphosphene)-palladium(0) (0.33g, 286 mmol) in dimethoxyethane (50 mL) was stirred under N₂ for 20minutes. To this mixture was then added lithium bromide (1.5 g, 172mmol). This solution was stirred under N₂ for 10 minutes. To thismixture was then added(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid(1.3 g, 5.7 mmol) and sodium carbonate (1.2 g, 11.5 mmol) in distilledwater (5 mL). The solution was brought to reflux for 6 hours, cooled toroom temperature, poured into distilled water and extracted with EtOAc(×3). The combined organic extracts were washed with 2N NaOH, water,brine, dried (MgSO₄), and evaporated. The residue was purified by columnchromatography (SiO₂, EtOAc:Hexane 2:5) to afford the title compound(0.6 g, 32%) as an off-white solid: mp 180-182° C.; ¹H-NMR (CDCl₃) δ8.21(s, 1H), 7.60 (d, 1H, J=1.8 Hz), 7.41 (dd, 1H, J=6.2, 1.9 Hz), 6.97 (d,1H, J=7.9 Hz), 6.88−6.86 (m, 1H), 6.84 (t, 1H, J=1.8 Hz), 6.59 (dt, 1lH, J=6.2, 2.2 Hz), 3.86 (s, 3H), 2.00−1.62 (m, 10H); MS ((−ESI)[M−H]⁻@m/z 324.

EXAMPLE 30

[0190] 5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0191] Prepared according to the procedure for example 14: mp. 196-198°C., ¹H NMR (CDCl₃) δ1.67-1.81 (m, 6H), 1.82-2.05 (m, 4H), 7.04 (d, 1H,J=8 Hz), 7.48 (dd, 1H, J=8 and 1 Hz), 7.59 (d, 1H, J=8 Hz), 7.63-7.65(m, 1H), 7.87-7.90 (m, 1H), 8.16-8.20 (m, 1H), 8.38 (s, br, 1H), 8.41(t, 1H, J=2 Hz); MS ((−)ESI) m/z 321 (M−H)⁻.

EXAMPLE 31

[0192] 3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)aniline

[0193] A solution of5′-(3-Nitrophenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (3.6 g,11 mmol) in methanol (150 ml) was shaken with 10% palladium on charcoal(1 g) under a hydrogen atmosphere at 40 psi. The catalyst was filteredoff and the solution was concentrated to obtain a residue. The residuewas dissolved in ether and ethanolic hydrochloric acid was added. Thesolid thus obtained was recrystallized from methanol/ether to obtain thetitle compound (1.7 g, 47%): m.p. 275-278° C.; ¹H-NMR (DMSO-d₆) δ1.5-2.0(m, 10H), 6.98 (d, J=8.05 Hz, 1H), 7.26 (d, J=7.90 Hz, 1H), 7.45-7.62(m, 4H), 7.67 (d, J=8.3 Hz, 1H), 9.0-11.0 (s, 2H, br), 10.5 (s, 1H), MS((+)APC1) m/z 293 (M+H).

EXAMPLE 32

[0194]5-(3-Fluoro-5-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0195] Prepared according to the procedure for example 18: mp. 191-193°C.; ¹H NMR (CDCl₃) δ1.66-2.07 (m, 10H), 7.07 (d, 1H, J=8 Hz), 7.49 (dd,1H, J=8, 1.8 Hz), 7.59-7.64 (m, 2H), 7.89 (dt, 1H, J=8.1, 2.1 Hz), 8.25(s, 1H) and 8.54 (s, 1H); MS ((+)−APCI) m/z 341 [M+H]⁺.

EXAMPLE 33

[0196] 5′-(3-Hydroxyphenyl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0197] Prepared according to the procedure for example 18: mp. 213-216°C.; ¹H NMR (CDCl₃) δ1.60-1.96 (m, 10H), 6.78-6.82 (m, 1H), 6.94 (d, 1H,J=8 Hz), 7.01-7.04 (m, 2H), 7.23 (t, 1H, J=7.7 Hz), 7.38 (d, 1H, J=8Hz), 7.61 (s, 1H), 8.91 (s, 1H) and 9.73 (s, 1H, br); MS ((+)−APCI) m/z294 [M+H]⁺.

EXAMPLE 34

[0198]4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile

[0199] 3-(Trimethylstannyl)-2-thiophenecarbonitrile

[0200] A solution of 3-bromo-2-thiophenecarbonitrile (0.8 g, 4.3 mmol),tetrakis(triphenylphosphine)palladium(0) (0.25 g, 0.2 mmol) andhexamethylditin (1.4 g, 4.3 mmol) in dimethoxyethane (5 cm³) was heatedunder reflux for 14 hours then cooled to room temperature. The reactionmixture was absorbed onto florisil and purified by column chromatography(SiO₂, methylene chloride: hexane 1:9) to afford the title compound(1.04 g, 3.8 mmol, 90%) as a clear viscous oil: ¹H NMR (CDCl₃) δ0.35 (s,9H), 7.56 (d, J=0.9 Hz, 1H), 7.66 (d, J=0.9 Hz, 1H).

[0201] A solution of the5′-bromospiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.53 g, 1.9mmol), dichlorobis(triphenylphosphine) palladium (II) (0.1 g, 0.14 mmol)and triphenylarsine (0.14 g, 0.47 mmol) in dimethoxyethane (8 cm³) wasstirred under N₂ for 20 min. To this mixture was then added3-(trimethylstannyl)-2-thiophenecarbonitrile (0.64 g, 2.35 mmol). Thesolution was brought to reflux for 32 h. After cooling to roomtemperature the reaction mixture was absorbed onto florisil and purifiedby column chromatography (SiO₂, ethyl acetate: hexane 2:3) to afford thetitle compound (0.43 g, 1.39 mmol, 74%) as an off white solid: ¹H NMR(CDCl₃) δ1.56-2.1 (m, 10H), 6.97 (d, J=8.0 Hz, 1H), 7.39 (dd, J=8.03,1.45 Hz, 1H), 7.57 (d, J=1.45 Hz, 1H), 7.59 (d, J=1.4 Hz, 1H), 7.84 (d,J=1.4 Hz, 1H), 8.32 (br s, 1H); ¹³C-NMR (CDCl₃) δ22.07, 26.56, 34.4 (t),48.13 (s), 110.18 (d), 111.3, 114.75 (s), 122.92, 126.76 (d), 128.44(s), 137.55 (d), 138.11, 142.71, 144.49, 182.13 (s); MS (EI) m/z 307(M−H)⁺.

EXAMPLE 35

[0202]5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl-2-thiophenecarbonitrile

[0203] 5-Bromo-2-thiophenecarbonitrile.

[0204] A mixture of 5-bromo-2-thiophenecarboxoaldehyde (96.0 g, 500mmol), hydroxylamine hydrochloride (111.9 g, 500 mmol), pyridine (500mL), and ethanol (500 mL) was heated under nitrogen at reflux for twohours. The reaction mixture was cooled to ambient temperature andconcentrated in vacuo to give an oil. The crude product was trituratedtwice with ice water and the solid obtained was collected on a filter. Amixture of a portion of the above solid (44.31 g, 215 mmol), copper (II)acetate monohydrate (4.2 g, 21 mmol) in acetonitrile (1.4L) was heatedat reflux for three hours. The solvent was removed in vacuo and theresidue was dissolved in ethyl acetate. The solution was washed with 5%aqueous sulfuric acid (2×30 mL), water (2×30 mL), brine (20 mL), anddried (MgSO₄). The solvent was removed in vacuo and the residue wasdissolved in a minimum amount of chloroform (1L) and allowed tocrystallize. The crystal obtained was collected on a filter and thefiltrate was concentrated and purified by a chromatography (silica gel,chloroform) to give the subtitled compound as an off-white solid (31.5 gcombined, 58%).: IR (film) cm⁻¹ 2200; ¹H-NMR (CDCl₃) δ7.39−7.38 (d, 1H,J=4.1 Hz), 7.10 (d, 1H, J=4.0 Hz); MS (EI) m/z 187 (M⁺, 98%) 189(M⁺,100%).

[0205] The title compound was prepared according to the procedure forexample 18 using 5-bromo-2-thiophenecarbonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronicacid: mp. 225-228° C.; 1H NMR (DMSO-d₆) δ1.63 (m, 8H), 1.90 (m, 2H) 6.91(d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.13, 1.76 Hz), 7.60 (d, 1H, J=4.17Hz), 7.75 (d, 1H, J=1.76 Hz), 7.93 (d, 1H, J=4.17 Hz), 10.51 (s, 1H); MS((+)APC1) m/z 309 [M+H]⁺.

EXAMPLE 36

[0206]4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

[0207] Prepared according to the procedure for example 18: m.p. 200-203°C.; ¹H NMR (DMSO-d₆) δ1.63 (m, 8H), 1.87 (m, 2H), 2.27 (s, 3H), 6.95 (d,1H, J=8.13 Hz), 7.34 (dd, 1H, J=8.13, 1.98 Hz) 7.54 (d, 1H, J=1.98 Hz),7.82 (s, 1H) 10.50 (s, 1H); MS ((+)APC1) m/z 323 [M+H]⁺.

EXAMPLE 37

[0208]4-Ethyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

[0209] Prepared according to the procedure for example 18: mp 214-217°C. ¹H NMR (DMSO-d₆) δ10.55 (s, 1H), 7.95 (s, 1H), 7.51 (s, 1H),7.33−7.30 (m, 1H), 6.98−6.96 (d, 2H J=8.0 Hz), 2.67−2.62 (m, 2H),1.89−1.86 (m, 2H), 1.69−1.55 (m, 8H), 1.20−1.15 (t, 3H); MS ((+)APCI)m/z 337 [M+H]⁺. Anal.Calc. For C₂₀H₂₀N₂O.½H₂O: C, 69.54;H, 6.13 ; N,8.11. Found: C, 69.51 ;H, 6.06; N, 7.57.

EXAMPLE 38

[0210]5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-3-carbonitrile

[0211] Prepared according to the procedure for example 18: m.p. 188-190°C.; ¹H-NMR (DMSO-d₆) δ1.5-2.0 (m, 10H), 6.89 (d, J=7.91 Hz, 1H), 7.49(dd, J=7.91, 1.98 Hz, 1H), 7.75 (d, J=1.76 Hz, 1H), 7.86 (d, J=1.32 Hz,1H), 8.44 (d, J=1.32 Hz, 1H); MS (−ESI) m/z 307 (M−H).

EXAMPLE 39

[0212]2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-thiophene-2-carbonitrile

[0213] Prepared according to the procedure for example 18: m.p. 207-9°C.; ¹H-NMR (DMSO-d₆) δ1.4-2.0 (m, 10H), 7.0 (d, J=8.13 Hz, 1H), 7.48 (d,J=5.27 Hz, 1H), 7.54 (dd, J=8.13 Hz, 1.98 Hz, 1H), 7.71 (d, J=5.49 Hz,1H), 7.85 (d, J=1.76 Hz, 1H), 10.6 (s, 1H); MS (−ESI) m/z 307 (M−H).

EXAMPLE 40

[0214]5-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-3-furancarbonitrile

[0215] Prepared according to the procedure for example 18: m.p. 243-245°C. ¹H-NMR (DMSO-d₆) δ10.48 (s, 1H), 8.62 (d, 1H J=0.7 Hz), 7.76 (d, 1HJ=1.5 Hz), 7.58−7.55 (dd, 1H), 7.33 (d, 1H J=0.7 Hz), 6.92−6.90 (d, 1HJ=8.1 Hz), 1.87−1.83 (m, 2H), 1.73−1.53 (m, 8H). MS ((+)EI) m/z 292(M+).

EXAMPLE 41

[0216] 5-(5-Chloro-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0217] Prepared according to the procedure for example 18: m.p. 191-192°C.; ¹H NMR (CDCl₃) δ1.6-2.1 (m, 10H), 6.85-6.95 (m, 2H), 6.98 (d, J=4.0Hz, 1H), 7.36 (dd, J=7.5, 1.6 Hz, 1H), 7.53 (d, J=0.9 Hz, 1H), 7.80 (brs, 1H); ¹³C-NMR (THF-d₈) δ21.35, 25.33, 33.12 (t), 48.32 (s), 110.40,121.66, 121.96, 125.44, 127.25 (d), 128.17, 128.43, 136.92, 140.20,143.43, 183.72 (s); MS (EI) m/z 318 (M+H)⁺.

EXAMPLE 42

[0218] 5-(5-Acetyl-2-thienyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0219] Prepared according to the procedure for example 18: m.p. 195-196°C., ¹H NMR (CDCl₃) δ1.6-2.1 (m, 10H), 2.58 (s, 3H), 6.95 (d, J=8.1 Hz,1H), 7.25 (d, J=4.0Hz, 1H), 7.54 (dd, J=8.1, 1.7 Hz, 1H), 7.66 (d, J=4.0Hz, 1H), 7.7 (d, J=1.7 Hz, 1H), 7.9 (br s, 1H); ¹³C NMR (CDCl₃) 22.24,26.19 (t), 27.59 (q), 33.99 (t), 49.02 (s), 111.39, 123.45, 124.12,127.02 (d), 128.59 (s), 134.79 (d), 137.92, 142.23, 143.41, 154.47,184.51, 191.76 (s); MS (EI) m/z 326 (M+H)⁺.

EXAMPLE 43

[0220]5-(2′-oxo-1′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′yl)-2-nitro-thiophene

[0221] Prepared according to the procedure for example 11: mp. 242° C.(decomp.); ¹H NMR (DMSO-d₆) δ1.62-1.67 (m, 6H), 1.90-1.99 (m, 2H), 6.94(d, 1H, J=8.1 Hz), 7.64 (d, 1H, J=4.5 Hz), 7.67 (dd, 1H, J=8.2, 1.8 Hz),7.86 (d, 1H, J=1.5 Hz), 8.15 (d, 1H, J=4.5 Hz), 10.62 (s, 1H); MS (EI)m/z 328 (M)⁻.

EXAMPLE 44

[0222]5′-(5-Nitro-1H-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2(1H)-one

[0223]2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1.3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

[0224] To a solution of 5′-bromo-spiro[cyclohexane-1,3′-indolin]-2′-one(3.4 g, 12 mmol) in 1,2-DME (100 mL) under a nitrogen atmosphere wasadded tetrakis(triphenylphospine)palladium(0) (70 mg, 5 mol %). After 15min, 2-borono-1H-pyrrole-1-carboxylic acid, 1-tert butyl ester (1.3 eq,3.31 g, 15.6 mmol) and a solution of K₂CO₃ (2.3 eq, 3.83 g, 27.6 mmol)in water (5 mL) were added sequentially. The solution was heated to 80°C. for 3 h and allowed to cool. The reaction mixture was poured intowater (200 mL) and extracted with EtOAc (2×100 mL). The organic layerswere combined, washed with brine (150 mL) and dried over MgSO₄. Thesolution was filtered, concentrated in vacuo, and the residue waspurified by flash column chromatography on silica gel (eluting with 30%EtOAc/hexane) to give subtitled compound: (3.4 g, 76%) as a whitepowder, mp 177° C. ¹H NMR (CDCl₃; 300 MHz) δ1.38 (s, 9 H), 1.59-1.93 (m,10 H), 6.18 (m, 1 H) 6.23 (‘t’, 1H, J=3 Hz), 6.91 (d, 1 H, J=8 Hz), 7.21(d, 1 H, J=8 Hz), 7.34 (m, 1 H), 7.44 (s, 1 H), 8.33 (br s, 1 H, D₂Oex).MS ((+)−APCI) m/z 367 [(M+H)⁺]. Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H,7.15; N, 7.64. Found: C, 71.7; H, 7.16; N, 7.5.

[0225]2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylicacid, tert-butyl carbamate.

[0226] To a solution of2-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (72 mg, 0.2 mmol) in MeCN (5 mL) at roomtemperature was added silver nitrate (1.05 eq, 35 mg, 0.2 mmol). After 5min, acetyl chloride (1.0 eq, 15 mg, 0.2 mmol) in MeCN (5 mL) was addedand the solution was allowed to stir for 16 h. Dichloromethane (10 mL)was added, and the solution was filtered through celite and washedsequentially with water, sat. NaHCO₃, water and brine (10 mL of each).The solution was dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(eluting with 40% EtOAc/hexane) to give the subtitled compound (56 mg,70%) as a yellow oil which crystallized from acetone/hexane, mp 163° C.(dec).

[0227]2-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-nitro-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.31 g, 0.85 mmol) was placed in a 5 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 200°C. After 5 min at this temperature, the flask was removed from the oilbath and allowed to cool. The black residue was washed into a largerflask with acetone and adsorbed onto a small amount of silica gel.Purification by flash column chromatography on silica gel (eluting with40% EtOAc/hexane) gave the title carbamate (0.20 g, 85%) as a yellow oilwhich crystallized from acetone/hexane, mp 278° C. (dec). ¹H NMR(DMSO-d₆; 300 MHz) δ1.55-1.87 (m, 10H), 6.80 (d, 1H, J=4 Hz), 6.91 (d,1H, J=8 Hz), 7.27 (d, 1H, J=4 Hz), 7.77 (dd, 1H, J=8, 1 Hz), 8.04 (d,1H, J=1 Hz), 10.51 (s, 1 H), 13.21 (br s, 1 H). MS ((+)−APCI) m/z 312[(M+H)⁺]. Anal. Calcd for C₁₇H₁₇N₃O₃: C, 65.58; H, 5.5; N, 13.5. Found:C, 65.57; H, 5.54; N, 13.44.

EXAMPLE 45

[0228]5′-(5-Nitro-1-methyl-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0229]5′-(1-Methyl-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0230] A mixture of5′-(1H-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.46g, 1.7 mmol) and potassium carbonate (5 eq, 1.18 g, 8.6 mmol) in DMF (2mL) at room temperature was treated with a solution of iodomethane (3eq, 0.32 g, 5.1 mmol) in DMF (1 mL). The solution was stirred 16 h atroom temperature, then poured into water (10 mL). EtOAc (15 mL) wasadded, the layers were separated, and the aqueous layer was extractedwith EtOAc (2×100 mL). The organic layers were combined, washed withbrine (15 mL) and dried over MgSO₄. The solution was filtered,concentrated in vacuo, and the residue was purified by flash columnchromatography on silica gel (eluting with 40% EtOAc/hexane) to give thesubtitled compound (0.44 g, 76%) as a white powder, mp 148-9° C. ¹H NMR(DMSO-d₆; 400 MHz) δ1.50-1.62 (m, 3 H), 1.62-1.82 (m, 5 H), 1.83-1.94(m, 2 H), 3.11 (s, 3 H), 6.08 (m, 1H), 6.42 (m, 1 H), 6.79 (m, 1 H),6.97 (d, 1 H, J=8.1 Hz), 7.51 (dd, 1 H, J=8.1, 1.8 Hz), 7.70 (d. 1 H,J=1.7 Hz), 11.20 (br s, 1 H). Anal. Calcd for C₁₈H₂₀N₂O₁: C, 77.11; H,7.19; N, 9.98. Found: C, 76.44; H, 7.21; N, 9.96.

[0231] A mixture of5′-(1-methyl-pyrrole-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one(0.36 g, 1.3 mmol) and silver nitrate (1.1 eq, 0.24 g, 1.4 mmol) inacetonitrile (10 mL) at room temperature was treated with acetylchloride (1.1 eq, 0.1 mL, 1.4 mmol). The mixture was stirred 1 h at thistemperature and then dichloromethane (30 mL) was added and the mixturewas filtered through celite. The organic phase was washed sequentiallywith water (20 mL), sat. aq. NaHCO₃ (20 mL), and brine (20 mL). Thesolution was dried over MgSO₄, filtered, and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(eluting with 40% EtOAc/hexane) to give the title compound (21 mg, 5%)as a yellow powder, mp 210° C. ¹H NMR (DMSO-d₆; 300 MHz) δ1.55-1.97 (m,10H), 3.15 (s, 3H), 6.77 (dd, 1H, J=4.2, 2.3 Hz), 7.05 (d, 1H, J=8.2Hz), 7.21 (dd, 1H, J=4.2, 2.3 Hz), 7.83 (dd, 1H, J=1.8, 8.2 Hz), 8.0 (d,1H, J=1.8 Hz), 13.0 (br s, 1H). MS ((+)−APCI) m/z 326 [(M+H)⁺]. Anal.Calcd for C₁₈H₁₉N₃O₃: C, 65.45; H, 5.89; N, 12.91. Found: C, 64.66; H,5.76; N, 12.52.

EXAMPLE 46

[0232] 5′-(1H-Indol-4-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0233] Prepared according to the procedure for example 18: mp 211-213°C.; ¹H-NMR (CDCl₃) δ8.32 (s, 1H), 7.84 (s, 1H), 7.81 (d, 1H, J=1.8 Hz),7.55 (dd, 1 H, J=6.2, 1.8 Hz), 7.40 (dt, 1H, J=6.2, 1.0 Hz), 7.29−7.28(m, 1H), 7.27 (t, 1H, J=3.1 Hz), 7.18 (dd, 1H, J=6.4, 0.9 Hz), 7.00 (dd,1H, J=7.5, 0.4 Hz), 6.72−6.71 (m, 1H), 2.00−1.59 (m, 10H); MS ((+)APCI)[M+H]⁺@m/z 317.

EXAMPLE 47

[0234] 3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol-5′-yl)benzonitrile

[0235] A solution of3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehydeoxime (0.48 g, 1.49 mmol) in chloroform (10 cm³) was treated withselenium dioxide (0.38 g, 3.50 mmol) and heated under reflux. After 16h, the mixture was concentrated and the residue purified by columnchromatography (SiO₂, EtOAc: hexane 1:4) and the product re-crystallizedfrom EtOAc-hexane to afford the title compound (0.161 g, 0.53 mmol, 35%)as a white solid: mp. 190-191° C.; ¹H NMR (CDCl₃) δ1.59-1.87 (m, 6H),1.88-2.09 (m, 4H), 7.03 (d, 1H, J=8 Hz), 7.42 (dd, 1H, J=8, 2 Hz), 7.54(t, 1H, J=8 Hz), 7.58-7.65 (m, 2H), 7.78 (dt, 1H, J=7, 2 Hz), 7.83 (m,1H), 8.26 (s, 1H, br); MS ((+) ESI) m/z 303 (M+H)⁺.

EXAMPLE 48

[0236]3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-fluorobenzonitrile

[0237] To a solution of 3,5-dibromofluorobenzene in diethyl ether (100cm³) at −78° C. was added n-butyl lithium (2.5 M, 8 cm³, 20 mmol)dropwise. After 30 min. the mixture was treated with DMF (20 cm³) indiethyl ether (10 cm³) and stirring was continued at −78° C. After 30min. the mixture was quenched with dilute HCl aq., separated and theaqueous layer was extracted with EtOAc. The combined organic layers werecombined, washed with water, brine, dried (MgSO₄) and evaporated to give3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: ¹H NMR(CDCl₃) δ inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H);MS (EI) m/z 202, 204 [M⁺].

[0238] To a solution of the last cited compound (4.0 g, 19.7 mmol) inethanol:water (8:2, 50 cm³), was added sodium acetate (1.72 g, 21 mmol)and hydroxylamine hydrochloride (1.45 g, 21 mmol), and the mixture washeated under reflux. After 30 min., the mixture was cooled, evaporatedand the residue partitioned between water and EtOAc. The aqueous layerwas re-extracted with EtOAc and the combined organic layers were washedwith water, saturated sodium hydrogen carbonate solution, brine, dried(MgSO₄) and evaporated to give 3-fluoro-5-bromobenzaldehyde oxime (3.76g, 17.24 mmol, 87%) which was used without further purification: 1H NMR(CDCl₃) δ7.24-7.27 (m, 2H), 7.50 (s, 1H), 7.68 (s, 1H) and 8.04 (s, 1H);MS (EI) m/z 217 [M⁺].

[0239] The above oxime (3.76 g, 17.24 mmol) and copper (II) acetate (370mg) were dissolved in acetonitrile (100 cm³) under nitrogen and heatedunder reflux. After 5 h, the mixture was evaporated, the residue takeninto EtOAc, washed with sulfuric acid (1N), water, brine, dried (MgSO₄)and evaporated to give 3-fluoro-5-bromobenzonitrile (3.08 g, 15.39 mmol,89%) which was used without further purification.

[0240] The above bromide (3.0 g, 15 mmol) andtetrakis(triphenylphosphine)palladium (0) (0.86 g, 0.75 mmol) weredissolved in dimethoxyethane (130 cm³) under nitrogen. After 15 min.(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid(2.82 g, 11.5 mmol) and sodium carbonate (3.1 g, 29.3 mmol) dissolved inwater (40 cm³) were added, and the mixture heated under reflux. After 8h the mixture was cooled, poured into water and extracted with EtOAc(×3). The combined organic layers were then washed with water, dried(MgSO₄) and evaporated. The residue was then purified by columnchromatography (EtOAc: hexane, gradient elution), and the productrecrystallized from methanol to give3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-5-flurobenzonitrile(1.78 g, 5.55 mmol, 48%): mp 199-205° C.; ¹H NMR (CDCl₃) δ1.64-2.03 (m,10H), 7.03 (d, 1H, J=8 Hz), 7.31 (dt, 1H, J=7.7 and 1.6 Hz), 7.41 (dd,1H, J=8, 1.7 Hz), 7.49 (dt, 1H, J=9.6, 2 Hz), 7.58 (d, 1H, J=2 Hz), 7.64(s, 1H) and 8.37 (s, 1H): MS (EI) m/z 320 [M⁺].

EXAMPLE 49

[0241]3-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-fluorobenzonitrile

[0242] Prepared according to the procedure for example 18: m.p. 205-206°C. ¹H NMR (DMSO-d₆) δ10.47 (s, 1H), 8.08−8.06 (dd, 1H), 7.89-7.85 (m,1H), 7.65 (s, 1H), 7.54−7.49 (m, 1H), 7.43−7.40 (tt, 1H), 6.95−6.93 (d,1H J=7.9 Hz), 1.97−1.83 (m, 2H), 1.69−1.55 (m, 8H); MS (EI) m/z 320 (M⁺)

EXAMPLE 50

[0243]3-(1′-Diethoxymethyl-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile

[0244] A solution of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-flurobenzonitrile(1.0 eq, 0.27 g, 0.84 mmol) in triethylorthoformate (2 mL, 12 mmol) washeated to 150° C. for 1 h. The reaction mixture was allowed to cool, theexcess triethylorthoformate was removed in vacuo, and the residue waspurified by flash column chromatography on silica gel (eluting with 10%EtOAc/hexane) to give the title compound (0.2 g, 56%) as a white powder,mp 146° C. ¹H NMR (DMSO-d₆; 400 MHz) δ1.13 (t, 6 H, J=7 Hz), 1.60-1.96(m, 10 H), 3.48 (m, 2 H), 3.66 (m, 2 H), 6.17 (s, 1H), 7.35 (d, 1H,J=8.3 Hz), 7.68 (dd, 1H, J=2.0, 8.3 Hz), 7.77 (ddd, 1 H, J=1.3, 2.4 Hz),7.89 (d, 1H, J=2.0 Hz), 7.92 (dt, 1 H, J=2.4, 10.5 Hz), 8.08 (dd, 1H,J=1.3, 2.9 Hz). MS ((+)−EI) m/z 422 [M⁺]. Anal. Calcd for C₂₅H₂₇FN₂O₃:C, 71.07; H, 6.44; N, 6.63. Found: C, 70.75; H, 6.48; N, 6.52.

EXAMPLE 51

[0245]3-(7′-Bromo-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile

[0246] A mixture of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(0.40 g, 1.23 mmol) and potassium acetate (0.13 g, 1.3 mmol) in glacialacetic acid (3 mL) at room temperature was treated with a solution ofbromine (1.05 eq, 0.21 g, 1.3 mmol) in a glacial acetic acid (3 mL).After stirring for 1 h the mixture was poured onto ice (20 g). Thelayers were separated and the aqueous layer was extracted withdichloromethane (2×10 mL). The organic layers were combined, washedsequentially with 10% aqueous sodium thiosulfate (20 mL), water (2×10mL), saturated sodium bicarbonate (10 mL) and brine (15 mL) and driedover MgSO₄. The solution was filtered, concentrated in vacuo, and theresidue was purified by flash column chromatography on silica gel(eluting with 30% EtOAc/hexane) to give the title compound (0.21 g, 43%)as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp 217°C. ¹H NMR (CDCl₃; 300 MHz) δ1.56-2.04 (m, 10 H), 7.33 (dddd, 1 H,J=1.25, 2.3, 3.6 and 9.0 Hz), 7.45 (m, 1 H), 7.47 (m, 2 H), 7.54 (m,1H), 7.60 (m, 1 H). MS ((−)−ESI) m/z 399 [M⁻]. Anal. Calcd forC₂₀H₁₆BrFN₂O₁: C, 60.17; H, 4.04; N, 7.02. Found: C, 60.03; H, 4.08; N,6.83.

EXAMPLE 52

[0247]3-(7′-Nitro-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile

[0248] A mixture of3-(1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(0.19 g, 0.6 mmol) and silver nitrate 0.11 g, 0.6 mmol) intrifluoroacetic acid (5 mL) was stirred 1 h at room temperature and thenpoured onto ice (20 g). Ether (15 mL) was added, the layers wereseparated, and the aqueous layer was extracted with ether (3×10 mL). Theorganic layers were combined and washed sequentially with water (2×20mL), saturated aqueous NaHCO₃ (20 mL) and brine (15 mL) and dried overMgSO₄. The solution was filtered, concentrated in vacuo, and the residuewas purified by flash column chromatography on silica gel (eluting with20% EtOAc/hexane) to give the title compound (0.2 g, 94%) as a whitepowder, mp 196° C. ¹H NMR (DMSO-d₆; 400 MHz) δ1.46-1.58 (m, 1 H),1.62-1.77 (m, 5 H), 1.83 (m, 2 H), 1.92-2.20 (m, 2 H), 7.85 (dddd, 1H,J=1.3, 2.4, 3.7 and 8.6 Hz), 8.12 (dddd, 1 H, J=1.8, 2.4, 4.2 and 10.5Hz), 8.23 (m, 2 H), 8.36 (d, 1 H, J=2.0 Hz), 11.17 (bs, 1 H). MS((−)−APCI) m/z 365 [M⁻]. Anal. Calcd for C₂₀H₁₆FN₃O₃: C, 65.75; H, 4.41;N, 11.5. Found: C, 65.4; H, 4.54; N, 11.3.

EXAMPLE 53

[0249]3-(7′-Amino-1′,2′-dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluoro-benzonitrile

[0250] To a solution of3-(7′-nitro-1′,2′-dihydro-2′-oxospiro-[cyclohexane-1,3′-[3H]indol]-5′-yl)-5-fluorobenzonitrile(1.0 eq, 0.16 g, 0.4 mmol) in glacial acetic acid (4 mL) at roomtemperature was added a solution of tin (11) chloride dihydrate (0.25 g,1.1 mmol) in hydrochloric acid (2 mL). The yellow mixture was boiled for30 min at which point the yellow color disappeared. After cooling toroom temperature, 1N HCl (10 mL) and ether (20 mL) were added. Thelayers were separated and the aqueous phase was extracted with ether(2×20 mL). The organic layers were combined, washed sequentially withwater (2×20 mL), saturated aqueous NaHCO₃ (20 mL), and brine (20 mL).The solution was dried over MgSO₄, filtered, and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(eluting with 40% EtOAc/hexane) to give the title compound (70 mg, 50%)as an oil which crystallized upon addition of 10% EtOAc/hexanes, mp241-3° C. ¹H NMR (DMSO-d₆; 400 MHz) δ1.50-1.75 (m, 8H), 1.82-1.95(m,2H), 4.98 (s, 2H), 6.90 (d, 1H, J=1.8 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.75(m, 2H), 7.90 (‘s’, 1H), 9.96 (bs, 1H). MS ((+)−APCI) m/z 336 [(M+H)⁺].Anal. Calcd for C₂₀H₁₈FN₃O: C, 71.63; H, 5.41; N, 12.18. Found: C,71.16; H, 5.58; N, 12.18.

EXAMPLE 54

[0251]5-(3-cyano-4-fluorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0252] Prepared according to the procedure for example 18: mp. 239-242°C.; ¹H NMR (CDCl₃) δ1.64-1.82 (m, 6H), 1.88-2.04 (m, 2H), 7.00 (d, 1H,J=8 Hz), 7.29-7.31 (m, 1H), 7.36 (dd, 1H, J=8.8, 2 Hz), 7.54 (d, 1H,J=1.5 Hz), 7.73-7.78 (m, 2H) and 8.19 (s, 1H, br); MS ((+)-APCI) m/z 321[M+H]⁺.

EXAMPLE 55

[0253]5′-(3-Chlorophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one

[0254] A solution of 3,3-dimethylglutaric anhydride in dry THF (60 cm³)was added over 30 min. to lithium aluminum hydride in dry THF (300 cm³)under nitrogen at 0° C. The mixture was then brought gradually up-toreflux. After 3 h, the mixture was cooled, treated with water (3.3 cm³),sodium hydroxide solution (15%, 3.3 cm³) and water (9.9 cm³). Themixture was then filtered, the precipitate extracted with EtOAc (×3),and the combined organics evaporated to afford3,3-dimethyl-1,5-pentanediol (quantitative yield); ¹H NMR (CDCl₃) δ0.95(s, 6H), 1.57 (t, 4H, J=6.3 Hz), 3.75 (t, 4H, J=6.3 Hz).

[0255] A solution of 3,3-dimethyl-1,5-pentanediol (8.4 g, 63.5 mmol) indry pyridine (180 cm³) was cooled to 0° C. under nitrogen and treatedover 5 h with a solution of p-toluenesulfonyl chloride (26.7 g, 140mmol) in dry pyridine (100 cm³). The mixture was then allowed to warm upto room temperature. After 16 h, the mixture was poured into ice/waterand extracted with EtOAc (×3). The combined organics were washed withdil. HCl (30%), saturated sodium hydrogen carbonate, brine, dried(MgSO₄) and evaporated to afford1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate (19.8 g, 45 mmol) whichwas used without further purification: ¹H NMR (CDCl₃) δ inter alia 0.85(s, 6H), 1.56. (t, 4H, J=7.0 Hz), 2.45 (s, 6H), 4.02 (t, 4H, J=7.0 Hz),7.35 (d, 4H, J=8.0 Hz), 7.77 (d, 4H, J=8.0 Hz); MS ((+) APCI) m/z 441(M+H)⁺.

[0256] A solution of 1,5-bis-(3,3-dimethylpentane)-p-toluenesulfonate(53.0 g, 120 mmol) and sodium iodide (72.0 g, 480 mmol) was dissolvedwith stirring in dry acetone (500 cm³). After 16 h at reflux the mixturewas cooled, poured into water and extracted with diethylether (×3). Thecombined organic extracts were washed with water, dried (MgSO₄), andevaporated to afford 3,3-dimethyl-1,5-diiodopentane (41.3 g, 117 mmol)as a yellow oil that was used without further purification: ¹H NMR(CDCl₃) δ inter alia 0.90 (s, 6H), 1.87-1.91 (m, 4H), 3.09-3.15 (m, 4H).

[0257] A solution of oxindole (2.0 g, 15 mmol) dissolved in dry THF (50cm³) under nitrogen was cooled to −60° C. and treated withn-butyllithium (2.5 M in hexanes, 15 cm³, 37.5 mmol) followed byN,N,N′N′-tetramethylethylenediamine (5.66 g, 37.5 mmol). After 20 min.3,3-dimethyl-1,5-diiodopentane (15.8 g, 45 mmol) in dry THF (10 cm³) wasadded and the mixture was allowed to warm up to room temperature. After16 h, the mixture was poured into water, extracted with EtOAc (×3),washed with water, dilute HCl (10%), water, brine, dried (MgSO₄) andevaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc: hexane, 1:6) to affordspiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one (0.37 g, 1.62mmol, 11%): ¹H NMR (CDCl₃) δ1.08 (s, 3H), 1.10 (s, 3H), 1.23-1.30 (m,2H), 1.54-1.68 (m, 4H), 1.94-2.04 (m, 2H), 6.94 (d, 1H, J=7.7 Hz), 7.01(t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.7 Hz), 7.42 (d, 1H, J=7.4 Hz), 8.76(s, 1H, br); MS (EI) m/z 229 (M)⁺.

[0258] To a solution of the last cited compound (0.37 g, 1.62 mmol) andsodium acetate (0.14 g, 1.7 mmol) in acetic acid (5 cm³) was addedbromine (0.27 g, 1.7 mmol) in acetic acid (2 cm³). After 30 min. themixture was poured into sodium hydroxide solution (2N) and extractedwith dichloromethane (×2). The organic extracts were washed with water,dried (MgSO₄) and evaporated to afford5′-bromospiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one(0.435 g, 1.41 mmol, 87%) which was used without further purification:¹H NMR (CDCl₃) δ1.08 (s, 3H), 1.49-1.64 (m, 4H), 1.69-1.74 (m, 2H),1.89-1.98 (m, 2H), 6.77 (d, 1H, J=8.2 Hz), 7.33 (dd, 1H, J=8.2, 1.8 Hz),7.48 (d, 1H, J=1.7 Hz), 7.71 (s, 1H, br); MS ((+)APCI) m/z 308 (M+H)⁺.

[0259] The last cited compound (0.56 g, 1.81 mmol) andtetrakis(triphenylphosphine) palladium(0) (0.1 g, 0.08 mmol) weredissolved in dimethoxyethane (20 cm³) under nitrogen. After 20 min.3-chlorophenylboronic acid (0.57 g, 3.64 mmol) and sodium carbonate(0.97 g, 9.15 mmol) were added and the mixture heated under reflux.After 16 h the mixture was cooled, poured into water and extracted withEtOAc (×2). The combined organic layers were washed with sodiumhydroxide (2N), water, brine, dried (MgSO₄) and evaporated. The residuewas then subjected to column chromatography (SiO₂, EtOAc: hexanes, 1:5)to afford the title compound which was triturated with hexane to give asolid (0.26 g, 0.77 mmol, 43%): mp. 184-185° C.; ¹H NMR (CDCl₃) δ1.11(s, 6H), 1.57-1.80 (m, 6H), 1.45-2.03 (m, 2H), 6.98 (d, 1H, J=8.0 Hz),7.29-7.44 (m, 4H), 5.52-7.55 (m, 2H), 8.12 (s, 1H, br); MS ((+)APCI) m/z340 (M+H)⁺.

EXAMPLE 56

[0260]5′-(3-Nitrophenyl)spiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one

[0261] To a solution of5′-bromospiro[4,4-dimethylcyclohexane-1′,3′-[3H]indol]-2′(1′H)-one (0.29g, 0.95 mmol) in dimethoxyethane (15 cm³) was added tetrakis(triphenylphosphine)palladium(0) (0.053 g, 0.046 mmol). After 20 min.3-nitrophenylboronic acid (0.32 g, 1.9 mmol) and sodium carbonate (0.5g, 4.75 mmol) in water (7.5 cm³) and the mixture heated under reflux.After 16 h, the mixture was cooled, poured into water and extracted withEtOAc (×2). The combined organic layers were washed with sodiumhydroxide solution (2N), water, brine, dried (MgSO₄) and evaporated. Theresidue was then subjected to column chromatography (SiO₂, EtOAc:hexanes, gradient elution), then the product was triturated with hexaneto afford the title compound (0.12 g, 0.35 mmol, 37%) as a yellow solid:mp. 230-231° C.; ¹H NMR (CDCl₃) δ1.18-1.24 (m, 6H), 1.57-1.86 (m, 6H),1.94-2.03 (m, 2H), 7.03 (d, 1H, J=8.0 Hz), 7.48 (d, 1H, J=8.0 Hz),7.59-7.64 (m, 2H), 7.87 (d, 1H, J=7.7 Hz), 8.06 (s, 1H, br), 8.19 (d,1H, J=7.7 Hz), 8.40 (s, 1H); MS ((+)APCI) m/z 351 (M+H)⁺.

EXAMPLE 57

[0262]2,3,5,6-Tetrahydro-5-(3-nitrophenyl)spiro[3H-indole-3,4-[4H]pyran]-2(1H)-one

[0263] To a solution of sodium iodide (64 g, 0.43 mol) in acetone underN₂ was added 2-bromoethyl ether (20 g, 0.086 mol), causing a white solidto precipitate. After 16 h the mixture was filtered and the filtrateconcentrated. Dichloromethane was added to the residue which wasfiltered, the cake further washed with dichloromethane, the combinedorganic layers were dried (MgSO₄) and evaporated to give 2-iodoethylether (26.61 g, 0.0816 mol, 95%) as a colorless oil: ¹H NMR (CDCl₃)δ3.26 (t, 2H, J=7 Hz), 3.78 (t, 2H, J=7 Hz).

[0264] A solution of oxindole (5.00 g, 37.5 mmol) in anhydrous THF underN₂ was cooled to −20° C. n-butyllithium (2.5 M in hexanes, 30 cm³, 75.1mmol) was added drop-wise followed byN,N,N′N′-tetramethylethylenediamine (11.4 cm³). After 20 min. a solutionof 2-iodoethyl ether (36 g, 112 mmol) in anhydrous THF (20 cm³) wasadded slowly. The mixture was allowed to warm to room temperature, thenafter 16 h was brought to reflux. After 5 h the mixture was cooled thenpoured into water, extracted with EtOAc (×2), the combined organiclayers were washed with dil. HCl (pH 1), water (×2), dried (MgSO₄) andevaporated. The residue was purified by column chromatography (SiO₂,acetone: hexane 1:5) to afford the title compound (0.78 g, 3.82 mmol,10%) as a white solid: ¹H NMR (CDCl₃) δ1.84-1.95 (m, 4H), 3.91-3.96 (m,2H), 4.21-4.27 (m, 2H), 6.89-6.92 (m, 1H), 7.06 (t, 1H, J=7, 1 Hz), 7.22(t, 1H, J=7, 1 Hz), 7.35-7.38 (m, 1H).

[0265] A solution of the above product (0.78 g, 3.82 mmol) and sodiumacetate (0.32 g, 4.02 mmol) in acetic acid (10 cm³) was treated withbromine (0.64 g, 4.02 mmol) in acetic acid (2 cm³). After 30 min. themixture was poured into sat. sodium hydrogen carbonate solution andextracted with EtOAc (×2) washed with water, sat. sodium hydrogencarbonate solution, water, dried (MgSO₄), and evaporated to give thetitle compound (0.59 g, 2 mmol, 54%) as an off-white solid which wasused without further purification: ¹H NMR (CDCl₃) δ1.83-2.00 (m, 4H),3.91-4.03 (m, 2H), 4.22-4.32 (m, 2H), 6.86 (d, 1H, J=7 Hz), 7.38-7.45(m, 1H), 7.52 (d, 1H, J=1 Hz), 8.36 (s, 1H, br); MS ((+)ESI) m/z 282(M+H)⁺.

[0266] A solution of the above product (0.58 g, 2.04 mmol) andtetrakis(triphenylphosphine)palladium (0.11 g, 0.09 mmol) indimethoxyethane (16 cm³) was stirred under N₂ for 20 min. To thismixture was then added 3-nitrophenylboronic acid (0.63 g, 4.06 mmol) andpotassium carbonate (1.68 g) in water (7 cm³). After 3 h at reflux themixture was cooled, poured into water and extracted EtOAc (×3). Thecombined organic extracts were washed with water, brine, dried (MgSO₄)and evaporated. The residue was then subjected to column chromatography(SiO₂, EtOAc: hexane, 1:2) to provide the title compound (0.19 g, 0.58mmol, 28%). A sample which was further purified by preparative LC(Primesphere C18, 10 micron, 50×250 mm, MeCN: H₂O 46:54, 100 cm³/min.,RT 7.57 min.) had the following properties: mp>250° C., ¹H NMR(acetone-d₆) δ1.78-1.88 (m, 2H), 1.92-2.01 (m, 2H), 3.85-3.94 (m, 2H),4.12-4.23 (2H), 7.08-7.13 (m, 1H), 7.62-7.69 (m, 1H), 7.70-7.79 (m, 1H),7.92-7.97 (m, 1H), 8.13-8.23 (m, 2H), 8.45-8.51 (m, 1H), 9.55 (s, 1H,br); MS (EI) m/z 341 (M)⁺.

EXAMPLE 58

[0267] 5′-(5-Chloro-3-methylbenzo[b]thien-2-yl)spiro[cyclo-hexane-1,3′-[3H]indol]-2′(1′H)-one

[0268] A solution of the 2-bromo-5-chloro-3-methylbenzo[b]-thiophene(0.28 g, 1.1 mmol) and tetrakis-(triphenylphosphine) palladium (0.13 g,0.1 mmol) in dimethoxyethane (8 cm³) was stirred under N₂ for 20 min. Tothis mixture was then added(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronic acid(0.32 g, 1.3 mmol) and sodium carbonate (0.35 g, 3.3 mmol) in water (4cm³). The solution was brought to reflux for 12 h then cooled to RT,poured into water and extracted with EtOAc (3×50 cm³). The combinedorganic extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,CH₂Cl₂) to afford the title compound (0.18 g, 0.47 mmol, 45%) as a whitesolid: m.p. 256-258° C., ¹H NMR (DMSO-d₆) δ1.47-1.97 (m, 10H), 2.42 (s,3H), 6.99 (d, J=8.0 Hz, 1H), 7.39 (d, J=1.6 Hz, 1H), 7.42 (d, J=1.2 Hz,1H), 7.6 (s, 1H), 7.85 (d, J=1.9 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 10.53(s, 1H); ¹³C NMR (DMSO-d₆) δ12.84 (q), 20.96, 25.08, 32.88 (t), 47.23(s), 109.98, 121.99, 124.25, 124.71, 125.01 (d), 126.47, 126.59, 129.17,130.01, 136.51, 140.42, 141.79, 142.76, 181.74 (s); MS (EI) m/z 380(M−H)⁺.

EXAMPLE 59

[0269]5-(3-Fluoro-4-nitrophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0270] The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(3.2 g, 12.5 mmol) and 4-bromo-2-fluoro-nitrobenzene (3 g, 13.6 mmol) asdescribed for example 18 (0.7 g, 16%) as a yellow solid: mp. 213-215°C.; 1H NMR (DMSO-d⁶) δ1.5-1.8 (m, 8H), 1.8-2.0 (m, 2H), 6.96 (d, 1H,J=8.13 Hz), 7.68 (dd, 1H, J=8.13, 1.76 Hz), 7.74 (dd, 1 H, J=8.68, 1.76Hz), 7.86 (d, 1H, J=1.98 Hz), 7.92 (dd, 1H, J=13.4, 1.76 Hz), 8.18 (t,1H, J=8.46 Hz) and 10.52 (s, 1H); MS (EI) m/z=340 (M⁺).

EXAMPLE 60

[0271]4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile

[0272] A solution of 3-bromo-5-cyano-furan (0.75 g, 4.4 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.4 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.6g, 6.5 mmol) and sodium acetate (1.4 g, 13.1 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.45 g, 36%) as anoff-white solid. mp: 240-242° C.; ¹H NMR (DMSO-d₆) δ10.4 (s, 1H), 8.5(s, 1H), 8.2 (s, 1H), 7.7 (s, 1H), 7.5 (dd, 1H, J=1.5 6.5 Hz), 6.9 (d,1H, J=8.0 Hz), 2.0−1.6 (m, 10H); MS (EI) M⁺ @m/z 292.

EXAMPLE 61

[0273]5-[4-Fluoro-3-(trifluoromethyl)phenyl]spiro[cyclohexane-1.3-[3H]indol]-2(1H)-one

[0274] The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.5 g, 10 mmol) and 5-bromo-2-fluoro-trifluoromethylbenzene (2 g, 8mmol) as described for example 18, to afford the title compound (0.87 g,30%) as a solid: mp. 222° C.; ¹H NMR (DMSO-d₆) δ1.5-1.8 (m, 8 H),1.8-2.0 (m, 2 H), 6.92 (d, 1 H, J=8.13 Hz), 7.51 (dd, 1 H, J=8.13, 1.76Hz), 7.55 (dd, 1 H, J=10.54, 9.01 Hz) 7.72 (d, 1 H, J=1.76 Hz), 7.90(dd, 1 H, J=7.03, 2.20 Hz), 7.98 (m, 1 H) and 10.39 (s, 1 H); MS (EI)m/z 363 (M⁺).

EXAMPLE 62

[0275]5-[4-Fluoro-3-nitrophenyl]spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0276] The title compound was prepared from(2′-oxo-2,3-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)boronic acid(2.8 g, 11 mmol) and 5-bromo-2-fluoro-nitrobenzene (2.7 g, 12.2 mmol) asdescribed for example 18, to afford the title compound (2.5 g, 66%) as asolid: mp. 243-245° C.; ¹H NMR (DMSO-d₆) δ1.8-2.0 (m, 2H), 1.5-1.8 (m,8H), 6.94 (d, 1H, J=8.13 Hz), 7.55 (dd, 1H, J=8.01, 1.87 Hz), 7.63 (dd,J=10.98, 8.79 Hz), 8.07 (m, 1H), 8.30 (dd, 1H, J=7.14, 2.53 Hz) and10.43 (s, 1H); MS (ESI (neg)) m/z 339 (M−H)⁻.

EXAMPLE 63

[0277]5′-(4-Cyano-3-fluorophenyl)-spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one

[0278] A solution of 4-cyano-3-fluoro-bromobenzene (0.76 g, 3.8 mmol),and tetrakis(triphenylphosphine)palladium(0) (0.3 g) in ethylene glycoldimethyl ether (15 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.4g, 5.7 mmol) and sodium acetate (1.2 g, 11.4 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.45 g, 37%) as anoff-white solid. mp: 258-260° C.; ¹H NMR (DMSO-d₆) δ8.8 (s, 1H), 7.7−7.6(m, 2 H), 7.5 (td, 2H, J=0.9. 1.5, 5.7 Hz), 7.4 (dd, 1H, J=1.5, 8.8 Hz),7.0 (d, 1H, J=8.1 Hz), 2.0−1.6 (m, 10H); MS (−)APCI [M−H]⁻ @m/z 319.

EXAMPLE 64

[0279]2-fluoro-4-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime

[0280] A solution of 3-fluoro-4-bromobenzaldehyde oxime (0.5 g, 2.2mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethyleneglycol dimethyl ether (10 cm³) was stirred under N₂ for 20 minutes. Tothis mixture was then added(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.8g, 3.3 mmol) and sodium acetate (0.7 g, 6.5 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.25 g, 34%) as anoff-white solid. mp: 240-242° C.; ¹H NMR (DMSO-d₆) δ11.6 (s, 1H), 10.4(s, 1H), 8.2 (s, 1H), 7.8−7.7 (m, 2H), 7.6−7.5 (m, 3H), 6.9 (d, 1H,J=8.1 Hz), 2.0−1.6 (m, 10H); MS (EI) M⁺ @m/z 338.

EXAMPLE 65

[0281]5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′yl)-2-nitrothiophene

[0282] A solution of 2-bromo-5-nitrothiophene (0.6 g, 2.9 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0g, 4.3 mmol) and sodium acetate (1.0 g, 10.0 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.87 g, 96%) as a yellowsolid. mp: 264-266° C.; ¹H NMR (DMSO-d₆) δ10.6 (s, 1H), 8.1 (d, 1H,J=4.5 Hz), 7.7 (d, 1H, J=1.8 Hz) 7.6 (m, 2H), 6.9 (d, 1H, J=8.1 Hz),2.0−1.9 (m, 8H); MS (EI) M⁺ @m/z 314.

EXAMPLE 66

[0283] 5-(3-Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one

[0284] A solution of 5-bromo-3,3-dimethyl-1,3-dihydro-indol-2-one (0.35g, 1.46 mmol) and tetrakis(triphenylphosphine) palladium (0.13 g, 0.11mmol) in dimethoxyethane (10 cm³) was stirred under N₂ for 20 min. Tothis mixture was then added 3-chloro-4-fluorobenzene boronic acid (0.26g, 1.49 mmol) and potassium carbonate (0.62 g, 4.5 mmol) in water (5cm³). The solution was brought to reflux for 16 h then cooled to RT,poured into saturated ammonium chloride and extracted with EtOAc (×3).The combined organic extracts were dried (MgSO₄), and evaporated. Theresidue was purified by column chromatography (SiO₂, ethyl acetate:hexane 1:3) to afford the title compound (0.124 g, 0.43 mmol, 30%) as awhite solid: m.p. 206.5-207.8° C., ¹H NMR (DMSO-d₆) δ1.3 (s, 6H), 6.93(d, J=8.1 Hz, 1H), 7.45 (dd, J=8.9, 8.9 Hz, 1H), 7.5 (dd, J=8.1, 1.8 Hz,1H), 7.6 (ddd, J=8.9, 7.1, 2.2 Hz, 1H), 7.7 (d, J=1.8 Hz, 1H), 7.8 (dd,J=7.1, 2.2 Hz, 1H), 10.5 (s, 1H (EI) m/z 289/291 (M)⁺.

EXAMPLE 67

[0285] 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile

[0286] (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronicacid

[0287] To a solution of5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one (3.5 g, 14.6 mmol)in dry tetrahydrofuran (60 cm³) was added sodium hydride (60% dispersionin mineral oil, 0.59 g, 14.6 mmol). After 30 min. stirring at roomtemperature, the mixture was cooled to −78° C. and n-butyl lithium (2.5M in hexanes, 5.9 cm³, 14.6 mmol) was added slowly. After 30 min.tri-isopropyl borate (9 cm³, 38.9 mmol) was added and the mixture wasallowed to warm to room temperature. After 8 hrs. hydrochloric acid (IN,200 cm³) and ethylacetate (200 cm³)was added and the mixture stirred for20 min. The aqueous phase was extracted with ethylacetate, then thecombined organic layers were washed with water, brine, dried (Na₂SO₄)and evaporated. The residue was triturated with hexane and theprecipitate dried in vacuo to obtain(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(1.8 g, 8.8 mmol, 60%) as a yellow-white solid that was used withoutfurther purification. ¹H NMR (DMSO-d₆) δ1.23 (s, 6H), 6.81 (d, J=7.8 Hz,1H) 7.63 (d, J=7.8 Hz, 1H) 7.66 (s, 1H), 7.84 (s, 2H) 8.69 (s, 1H).

[0288] A solution of 3-bromobenzonitrile (0.30 g, 1.65 mmol) andtetrakis(triphenylphosphine) palladium (0.13 g, 0.11 mmol) indimethoxyethane (10 cm³) was stirred under N₂ for 20 min. To thismixture was then added the (2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid, (0.41 g, 2.0mmol) and potassium carbonate (0.86 g, 6.2 mmol) in water (5 cm³). Thesolution was brought to reflux for 16 h then cooled to room temperature,poured into saturated ammonium chloride and extracted with EtOAc (×3).The combined organic extracts were dried (MgSO₄), and evaporated. Theresidue was purified by column chromatography (SiO₂, ethyl acetate:hexane 1:2.5) to afford the title compound (0.22 g, 0.68 mmol, 51%) as awhite solid: m.p. 200.2-202.0° C., ¹H NMR (DMSO-d₆) δ1.32 (s, 6H), 6.96(d, J=8.1 Hz, 1H), 7.58 (dd, J=8.1, 1.8 Hz, 1H), 7.63 (dd, J=7.8, 7.8Hz, 1H), 7.75-7.78 (m, 2H), 7.98 (d, J=8.0 Hz, 1H), 8.15 (s, 1H), 10.49(s, 1H); MS (EI) m/z 263 (M+H)+.

EXAMPLE 68

[0289]2-fluoro-3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)benzaldehyde oxime

[0290] A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) indry methanol (5 ml) under nitrogen was treated withtrimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid(catalytic amount), and then heated under reflux. After 16 h, themixture was evaporated and the residue partitioned between water andEt₂O. The organic layer was washed with sat. sodium hydrogen carbonatesolution, water, brine, dried (MgSO₄) and evaporated to give methyl3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84%): ¹H NMR (CDCl₃)δ7.90−7.85 (m, 1H), 7.71−7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and3.94 (s, 3H): MS (EI) 232 (M⁺).

[0291] A solution of the last cited compound (3.077 g, 13.2 mmol) in drytoluene (80 ml) at −78° C. under nitrogen was treated withdi-iso-butylaluminum hydride in toluene (1M, 15.7 ml, 15.7 mmol). After1 h at −78° C., the mixture was quenched with aqueous HCl (3M, 16 ml).The mixture was warmed to room temperature (RT), partitioned betweenEtOAc/H₂O, the aqueous layer was re-extracted with EtOAc, and thecombined organic layers were washed with water, dried (MgSO₄) andevaporated to afford 3-bromo-2-fluorobenzaldehyde (2.63 g, 12.9 mmol,98%), which was used without further purification: ¹H NMR (CDCl₃) δ10.35(s, 1H), 7.82 (m, 2H), 7.18 (t, J=7.8 Hz).

[0292] A mixture of the last cited compound (2.63 g, 12.9 mmol),hydroxylamine hydrochloride (1.0 g, 14 mmol) and potassium acetate (1.37g, 14 mmol) was placed in ethanol/H₂O (60 ml, 8:2) and the mixture washeated under reflux. After 30 min. the mixture was cooled, evaporatedand partitioned between EtOAc and water. The organic layer was washedwith brine, dried (MgSO₄) and evaporated to give afford3-bromo-2-fluorobenzaldoxime which was used without furthercharacterization.

[0293] The title compound was prepared from 3-bromo-2-fluorobenzaldoxime(0.40 g, 1.83 mmol) and(spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid asdescribed in example 18, to afford the product (0.094 g, 0.27 mmol, 15%yield) as a white solid: mp. 213-217° C.; ¹H NMR (CDCl₃) δ10.95 (s, 1H),9.65 (s, 1H), 8.41 (s, 1H), 7.76 (t, 1H, J=7.1 Hz), 7.59 (s, 1H),7.43−7.33 (m, 3H), 7.19 (t, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8 Hz) and1.91−1.60 (m, 10H); MS ((+) ESI) m/z=339 [M+H]⁺.

EXAMPLE 69

[0294] 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile

[0295] 5-Bromo-4-methyl-2-thiophene carboxaldehyde. To a solution ofdiethylamine (28 g, 0.383 mol) in anhydrous THF (400 mL) was added at−40° C. under nitrogen a solution of n-BuLi (2.5 M, 153 mL, 0.383 mol)in hexane. After addition, the solution was stirred at −40° C. undernitrogen for 30 minutes, cooled to −78° C. and treated dropwise with asolution of 2-bromo-3-methylthiophene (45 g, 0.254 mol) in anhydrous THF(450 mL). The reaction solution was stirred at −78° C. for 30 minutesand treated with anhydrous DMF (100 mL). The mixture was allowed to warmto ambient temperature and was quenched with 1N aqueous hydrochloridesolution (1L). The solution was extracted with ethyl acetate(3×450 mL).The extracts were washed with water, brine and dried (MgSO₄). Afterremoval of solvent in vacuo, the subtitled compound was obtained as awhite solid (46g, 88.3%). A sample of the product was crystallized fromhexane: mp 63-65° C.; IR (KBr) 1654 cm⁻¹. ¹H-NMR (CDCl₃) δ9.75 (s, 1H),7.45 (s, 1H), 2.26 (s, 3H); MS (EI) m/z 204/206 (M⁺). Anal. Calc. ForC₆H₅BrOS: C, 35.14; H, 2.46. Found: C, 35.00; H, 2.44.

[0296] 5-Bromo-4-methyl-2-thiophenecarbonitrile. Prepared from5-bromo-4-methyl-2-thiophene carboxaldehyde using the procedure ofExample 35. White solid: mp 40-42° C.; IR (KBr) 2200 cm⁻¹; ¹H-NMR(CDCl₃) δ7.29 (s, 1H), 2.21 (s, 3H). MS (EI) m/z 201/203 (M⁺, 98%/100%);Anal. Calc. For C₆H₄BrNS: C, 35.66; H, 1.99; N, 6.93. Found: C, 36.00;H, 2.14; N, 6.76.

[0297] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(357 mg, 1.7 mmol) and 5-bromo-4-methylthiophene-2-carbonitrile (295 mg,1.5 mmol) to afford the title compound (227 mg, 0.8 mmol, 55%) as awhite solid: mp. 192.3-193° C., ¹H NMR (DMSO-d₆) δ1.29 (s, 6H), 2.29 (s,3H), 6.97 (d, J=8.0 Hz, 1H), 7.34 (dd, J=8.0, 1.8 Hz, 1H), 7.49 (d,J=1.7 Hz, 1H), 7.84 (s, 1H), 10.57 (s, 1H); MS (EI) m/z 282 (M)⁺.

EXAMPLE 70

[0298]5-(3-Chloro-5-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one,

[0299] Prepared according to the procedure for example 18 for using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(345 mg, 1.7 mmol) and 1-bromo-3-chloro-5-fluorobenzene (295 mg, 1.4mmol) to afford the title compound (245 mg, 0.85 mmol, 60%) as a whitesolid: mp. 205.9-206.8° C. ¹H NMR (DMSO-d₆) δ1.31 (s, 6H), 6.93 (d,J=8.1 Hz), 7.35 (d, J=8.6 Hz, 1H), 7.5-7.6 (m,2H), 7.6 (s, 1H), 7.78 (d,J=1.4 Hz, 1H), 10.49 (s, 1H); MS (EI) m/z 290 (M+H)⁺.

EXAMPLE 71

[0300] 5-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one,

[0301] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(272 mg, 1.3 mmol) and 1-fluoro-3-iodo-5-nitrobenzene (299 mg, 1.1 mmol)to afford the title compound (192 mg, 0.64 mmol, 57%) as a yellow solid:mp. 231.2-232.7° C., ¹H NMR (DMSO-d₆) δ1.33 (s, 6H), 6.97 (d, J=8.1Hz,1H), 7.67 (dd, J=8.1, 1.7Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 8.0-8.1 (m,2H), 8.32 (s,1H), 10.55 (s, 1H);

MS (ESI) m/z 301 (M+H)⁺.

EXAMPLE 72

[0302]4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile

[0303] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(354 mg, 1.7 mmol) and 4-bromo-furan-2-carbonitrile (200 mg, 1.2 mmol)to afford the title compound (76 mg, 0.3 mmol, 26%) as a white solid:mp. 199.6-201.4° C., ¹H NMR (DMSO-d₆) δ1.28 (s, 6H), 6.89 (d, J=8.0 Hz,1H), 7.48 (dd, J=8.0, 1.8 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 8.1 (s, 1H),8.5 (s, 1H), 10.46 (s, 1H); MS (ESI) m/z 251 (M−H)⁻.

EXAMPLE 73

[0304]4-Methyl-5-(2′-oxo-2′,3′-dihydrospiro[cyclopentane-1,3′-[3H]indol]-5′-yl)-2-thiophenecarbonitrile

[0305] (Spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronicacid

[0306] To a solution of5-bromo-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one (13.1 g, 53 mmol)in anhydrous THF (300 cm³) under N₂, was added sodium hydride (60% inmineral oil, 2.1 g, 53 mmol). After 30 minutes, the reaction mixture wascooled to −78° C. and butyl lithium (2.5 M in hexanes, 22 cm³, 53 mmol)was added slowly. After 30 minutes, tris-iso-propylborate (34 cm³, 146mmol) was added, and the reaction mixture was slowly brought to roomtemperature, and stirred for 14 hours. The reaction mixture was pouredinto 1N HCl and extracted with EtOAc (×3). The organic layers werecollected and washed with 1N HCl, water, dried (MgSO₄) and evaporated togive the subtitled compound (7.8 g, 64%) as a tan solid which was usedwithout further purification. ¹H NMR (DMSO-d₆) δ10.3 (s, 1H), 7.9 (s,1H), 7.7−7.6 (m, 2H), 6.8 (d, 1H, J=7.7 Hz), 3.4 (s, 1H), 2.0−1.7 (m,8H); MS (FI-POS) m/z @231.

[0307] A solution of 2-bromo-5-cyano-3-methylthiophene (0.63 g, 3.1mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethyleneglycol dimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. Tothis mixture was added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.6 g, 62%) as apale-yellow solid. mp: 135-136° C.; ¹H NMR (DMSO-d₆) δ10.5 (s, 1H), 7.8(s, 1H), 7.4−7.3 (m, 2H), 7.0 (d, 1H, J=8.0 Hz), 2.3 (s, 3H), 2.0−1.8(m, 8H); MS [M−H]⁻=307.

EXAMPLE 74

[0308]5′-(4-Cyano-3-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0309] A solution of 4-cyano-3-fluoro-bromobenzene (0.63 g, 3.1 mmol),and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 36%) as a yellowsolid. mp: dec. @235° C.; ¹H NMR (DMSO-d₆) δ10.5 (s, 1H), 7.9 (t, 1 H,J=7.6 Hz), 7.9 (dd, 1H, J=1.4, 10.2 Hz), 7.3 (td, 2H, J=1.6, 6.5 Hz),7.6 (dd, 1H, J=1.9, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0−1.9 (m, 8H); MS[M−H]⁻=305.

EXAMPLE 75

[0310] 5′-(3-cyano-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0311] A solution of 3-cyano-4-fluoro-bromobenzene (0.63 g, 3.1 mmol),and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0g, 4.7 mmol) and sodium acetate (1.0 g, 9.4 mmol) in water (5 cm³). Thesolution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.10 g, 10%) as whitecrystals. mp: 264-266° C.; ¹H NMR (DMSO-d₆) δ10.4 (s, 1H), 8.3 (dd, 1 H,J=2.4, 3.7 Hz), 8.1−8.0 (m, 1H), 7.6−7.5 (m, 2H), 7.5 (dd, 1H, J=1.9,6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0−1.9 (m, 8H); MS [M−H]⁻=305.

EXAMPLE 76

[0312]5′-(3-Chloro-4-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0313] A solution of 3-chloro-4-fluoro-bromobenzene (0.4 cm³, 0.66 g,3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.2 g) inethylene glycol dimethyl ether (20 cm³) was stirred under N₂ for 20minutes. To this mixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (1.0g, 4.7 mmol) and sodium carbonate (1.0 g, 9.4 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.65 g, 66%) as apale-yellow solid. mp: 202-204° C.; ¹H N (DMSO-d₆) δ10.4 (s, 1H), 7.9(dd, 1H, J=2.3, 4.9 Hz), 7.7−7.6 (m, 1H), 7.6 (d, 1H, J=1.5 Hz), 7.5 (s,1H), 7.4 (d, 1H, J=1.8 Hz), 6.9 (d, 1H, J=8.0 Hz), 2.0−1.9 (m, 8H); MS[M−H]⁻=314.

EXAMPLE 77

[0314] 5′-(3-Cyanophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0315] A solution of 3-bromobenzonitrile (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.30 g, 40%) as anoff-white solid. mp: 217-219° C.; ¹H NMR (DMSO-d₆) δ10.4 (s, 1H), 8.2(s, 1H), 8.0 (d, 1H, J=8.1 Hz), 7.8 (d, 1H, J=7.7 Hz), 7.6 (m, 2H), 7.5(dd, 1H, J1.8, 6.3 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0−1.9 (m, 8H); MS[M−H]⁻=287.

EXAMPLE 78

[0316]5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-thiophenecarbonitrile

[0317] A solution of 2-bromo-5-cyanothiophene (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.3 g, 40%) as a yellowsolid. mp: 248° C; ¹H NMR (DMSO-d₆) δ10.4 (s, 1H), 8.5 (d, 1H, J=1.4Hz), 8.3 (d, 1H, J=1.4 Hz), 7.6 (s, 1H), 7.5 (dd, 1H, J=1.7, 6.4 Hz),6.9 (d, 1H, J=8.1 Hz), 2.0−1.8 (m, 8H); MS [M−H]⁻=293.

EXAMPLE 79

[0318]5-(3.3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile

[0319] A solution of 5-cyano-2-bromofuran (0.5 g, 2.6 mmol), andtetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 49%) as anoff-white solid. mp: 193-194° C.; ¹H NMR (DMSO-d₆) δ10.6 (s, 1H), 7.7(d, 2H, J=3.3 Hz), 7.6 (dd, 1H, J=1.6, 6.6 Hz), 7.1 (d, 1H, J=3.8 Hz),6.9 (d, 1H, J=8.1 Hz), 2.0−1.8 (m, 8H); MS [M−H]⁻=277.

EXAMPLE 80

[0320]5′-(3-Cyano-5-fluorophenyl)-spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one

[0321] A solution of 3-cyano-5-fluoro-bromobenzene (0.5 g, 2.6 mmol),and tetrakis(triphenylphosphine)palladium(0) (0.2 g) in ethylene glycoldimethyl ether (20 cm³) was stirred under N₂ for 20 minutes. To thismixture was then added(spiro[cyclopentane-1,3′-[3H]indol]-2′(1′H)-one-5-yl) boronic acid (0.9g, 3.9 mmol) and sodium carbonate (0.8 g, 7.8 mmol) in water (5 cm³).The solution was brought to reflux for 18 hours and then cooled to roomtemperature, poured into 2N NaOH and extracted with EtOAc (×3). Thecombined extracts were washed with water, brine, dried (MgSO₄), andevaporated. The residue was purified by column chromatography (SiO₂,EtOAc, hexane) to afford the title compound (0.35 g, 44%) as whiteneedles. mp: 235-237° C.; ¹ H NMR (DMSO-d₆) δ10.5 (s, 1H), 8.1 (s, 1H),8.0 (dt, 1H, J=1.7, 2.0, 7.0 Hz), 7.8−7.7 (m, 2H), 7.6 (dd, 1H, J=1.8,6.4 Hz), 6.9 (d, 1H, J=8.1 Hz), 2.0−1.9 (m, 8H); MS (EI) M⁺ @m/z 306.

EXAMPLE 81

[0322]3-(1′,2′-Dihydro-2′-oxospiro[cyclohexane-1,3′-[3H]indol]-5′-yl)phenylacetonitrile

[0323] Prepared from 3-bromophenylacetonitrile and2′-oxo-2′,3,-dihydrospiro [cyclohexane-1,3′-[3H]indol]-5′-yl)boronicacid according to the procedure for example 18 to afford the titlecompound as a white powder; mp. 190-193° C.; ¹H-NMR (DMSO-d₆) δ10.42 (s,1H), 7.67 (d, 1H, J=1.39 Hz), 7.58 (d, 2H, J=6.87 Hz), 7.46 (m, 2H),7.31 (d, 1H J=7.6 Hz), 6.94 (d, 1H, J=8.05 Hz), 4.10 (s, 2H) 2.04−1.50(m, 10H); MS m/z 316(M+.). Anal. Calc. For C₂₁H₂₀N₂O₂ 0.2 H₂O: C, 78.82,H, 6.42, N, 8.75. Found: C, 78.73, H,6.44, N, 8.52.

EXAMPLE 82

[0324]3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-fluoro-benzonitrile

[0325] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(640 mg, 3.1 mmol) and 5-bromo-3-cyano-fluorobenzene (423 mg, 21.2 mmol)to afford the title compound (261 mg, 0.93 mmol, 44%) as a yellow solid:mp. 231.2-232.3° C., ¹H NMR (DMSO-d₆) δ1.32 (s, 6H), 6.95 (d, J=8.0 Hz,1H), 7.64 (dd, J=8.1, 1.8 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.85 (d,J=1.6 Hz, 1H), 7.93 (d, J=8.6 Hz, 1H), 8.07 (s, 1H), 10.52 (s, 1H); MS(EI) m/z 280 (M)⁺.

EXAMPLE 83

[0326] 3,3-Dimethyl -5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one,

[0327] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(384 mg, 1.9 mmol) and 2-bromo-5-nitrothiophene (300 mg, 1.4 mmol) toafford the title compound (270 mg, 0.9 mmol, 65%) as a yellow brownsolid: mp. 223-225° C., ¹H NMR (CDCl₃) δ1.5 (s, 6H), 6.99 (d, J=8.1 Hz,1H), 7.18 (d, J=4.3 Hz, 1H), 7.44 d, J=1.7 Hz, 1H), 7.51 (dd, J=8.1, 1.9Hz, 1H), 7.91 (d, J=4.3 Hz, 1H), 8.07 (br s, 1H); MS (EI) m/z 288 (M)⁺.

EXAMPLE 84

[0328]2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester

[0329] Prepared according to the procedure for example 18 using5′-bromo-3,3-dimethyl-[1,3′-[3H]indol]-2′-(1′H)-one (1.24 g, 5.2 mmol)and N-BOC-pyrrole-2-boronic acid (1.5 g, 5.93 mmol) to afford the titlecompound (506 mg, 1.5 mmol, 30%) as off-white solid: mp. 168.4-170.2°C., ¹H NMR (DMSO-d₆) δ1.26 (s, 6H), 1.28 (s, 9H), 6.1 (dd, J=3.2, 1.8Hz,1H), 6.2 (dd, J=3.2, 3.2Hz, 1H), 6.8 (d, J=7.9Hz, 1H), 7.1 (dd, J=7.9,1.6 Hz, 1H), 7.2 (d, J=1.6Hz, 1H), 7.3 (dd, J=3.2, 1.8 Hz, 1H), 10.4 (s,1H); MS (APCI) m/z 327 (M+H)+.

EXAMPLE 85

[0330] 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole

[0331] To a solution of2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylicacid tert-butyl ester (0.90 g, 2.8 mmol) in acetonitrile (anhydrous, 40mL) at −15° C. was added silver nitrate (0.49 g,, 2.9 mmol) followed byacetyl chloride (0.21 mL, 2.95 mmol). The reaction was allowed to warmto room temperature and stirred 16 h. Dichloromethane (250 mL) was addedto the reaction mixture; filtered through celite and washed with water,saturated sodium bicarbonate, water then brine dried over magnesiumsulfate, filtered and concentrated in vacuo. Purification via flashcolumn chromatography on silica gel (2:3 ethyl acetate/hexane) gave2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylicacid tert-butyl ester as a yellow solid: ¹H NMR (CDCl₃) δ1.43 (s, 6H),1.48 (s, 9H), 6.3 (d, J=4.1 Hz, 1H), 7.0 (d, J=8.0 Hz, 1H), 7.2 (d,J=4.1 Hz, 1H), 7.34 (d, J=1.7 Hz, 1H), 7.4 (dd, J=8.0, 1.7 Hz, 1H), 8.2(s, 1H).

[0332]2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole-1-carboxylicacid tert-butyl ester, was placed in a 50 mL round bottomed flask undernitrogen. A vigorous flow of nitrogen was maintained as the flask wasplaced in an oil bath and heated to 160° C. After 10 min at thistemperature, the flask was removed from the oil bath and allowed tocool. The black residue was washed into a larger flask with acetone andadsorbed onto a small amount of florisil. Purification by flash columnchromatography on silica gel (1:2 EtOAc:hexane) to afford the titlecompound (76 mg, 15%) which was triturated from ether/hexane to providea greenish-yellow solid, mp 293.9-294.2° C. (dec). ¹H NMR (DMSO-d₆) δ1.3(s, 6H), 6.77 (d, J=4.3 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 7.26 (d, J=4.3Hz, 1H), 7.78 (dd, J=8.1, 1.8 Hz, 1H), 7.96 (d, J=1.8 Hz, 1H), 10.55 (s,1H), 13.12 (s, 1H); MS (ESI) m/z 270 (M−H)⁻.

EXAMPLE 86

[0333]5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile

[0334] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(570 mg, 2.8 mmol) and 5-bromo-thiophene-2-carbonitrile (350 mg, 1.9mmol) to afford the title compound (299 mg, 1.1 mmol, 60%) as anoff-white solid: mp. 255-256° C., ¹H NMR (CDCl₃) δ¹H NMR (CDCl₃) δ1.46(s, 6H), 6.97 (d, J=8.1 Hz, 1H), 7.21 (d, J=3.9 Hz, 1H), 7.39 (d, J=1.3Hz, 1H), 7.47 (dd, J=8.1, 1.8 Hz, 1H), 7.58 (d, J=3.9 Hz, 1H), 8.14 (s,1H); MS (EI) m/z 268 (M)⁺.

EXAMPLE 87

[0335]3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile

[0336] Prepared according to the procedure for example 18 using(2′-oxo-[2,3-dihydro-3,3-dimethyl-1,3′-[3H]indol]-5′-yl) boronic acid(300 mg, 1.5 mmol) and 4-bromo-2-fluoro-benzonitrile (240 mg, 1.2 mmol)to afford the title compound (185 mg, 0.66 mmol, 55%) as an off whitesolid: mp. 270-272° C., ¹H NMR (DMSO-d₆) δ1.31 (s, 6H), 6.96 (d, J=8.1Hz, 1H), 7.67 (dd, J=8.1, 1.8 Hz, 1H), 7.74 (dd, J=8.2, 1.5 Hz, 1H),7.85 (s, 1H), 7.89 (d, J=1.3 Hz, 1H), 7.96 (dd, J=7.5, 7.5 Hz, 1H),10.56 (s, 1H); MS (ESI) m/z 279 (M−H)⁻.

EXAMPLE 88

[0337] Pharmacology

[0338] The biological activity for the compounds of the currentinvention was evaluated in the in-vitro and in-vivo assays describedbelow. In-vitro potencies lie in the range 0.01 nM-10,000 nM, andin-vivo potencies in the range 1 μg/kg to 100 mg/kg.

[0339] A. In-Vitro Biology

[0340] The in-vitro biology is determined by (1) competitive RadioligandBinding: using the A-form of the human progesterone receptor withprogesterone as the radioligand; (2) co-transfection assay, whichprovides functional activity expressed as agonist EC50 and AntagonistIC50 values; (3) a T47D cell proliferation, which is a furtherfunctional assay which also provides agonist and antagonist data; and(4) T47D cell alkaline phosphatase assay, which is a further functionalassay which also provides agonist and antagonist data.

[0341] 1. hPR Binding Assay

[0342] This assay is carried out in accordance with: Pathirana, C.;Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro, T.; Mais, D. E.;Torres, A.; Glodman, M. E., Nonsteroidal human progesterone receptormodulators from the marine alga cymoplia barbata, J. Steroid Biochem.Mol. Biol., 1992, 41, 733-738.

[0343] 2. PRE-Luciferase Assay in CV-1 Cells

[0344] The object of this assay is to determine a compound'sprogestational or antiprogestational potency based on its effect onPRE-luciferase reporter activity in CV-1 cells co-transfected with humanPR and PRE-luciferase plasmids. The materials methods used in the assayare as follows.

[0345] a. Medium:

[0346] The growth medium was as follows: DMEM (Bio Whittaker) containing10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows:DMEM (Bio Whittaker), phenol red-free, containing 10% (v/v)charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL).

[0347] b. Cell Culture, Transfection, Treatment, and Luciferase

[0348] Stock CV-1 cells are maintained in growth medium. Co-transfectionis done using 1.2×10⁷ cells, 5 mg pLEM plasmid with hPR-B inserted atSph1 and BamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of theluciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNAin 250 ml. Electroporation is carried out at 260 V and 1,000 mF in aBiorad Gene Pulser II. After electroporation, cells are resuspended ingrowth medium and plated in 96-well plate at 40,000 cells/well in 200μl. Following overnight incubation, the medium is changed toexperimental medium. Cells are then treated with reference or testcompounds in experimental medium. Compounds are tested forantiprogestational activity in the presence of 3 nM progesterone.Twenty-four hr. after treatment, the medium is discarded, cells arewashed three times with D-PBS (GIBCO, BRL). Fifty μl of cell lysisbuffer (Promega, Madison, Wis.) is added to each well and the plates areshaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).Luciferase activity is measured using luciferase reagents from Promega.

[0349] c. Analysis of Results:

[0350] Each treatment consists of at least 4 replicates. Log transformeddata are used for analysis of variance and nonlinear dose response curvefitting for both agonist and antagonist modes. Huber weighting is usedto downweight the effects of outliers. EC₅₀ or IC₅₀ values arecalculated from the retransformed values. IMP software (SAS Institute,Inc.) is used for both one-way analysis of variance and non-linearresponse analyses.

[0351] d. Reference Compounds:

[0352] Progesterone and trimegestone are reference progestins and RU486is the reference antiprogestin. All reference compounds are run in fulldose-response curves and the EC₅₀ or IC₅₀ values are calculated. TABLE 1Estimated EC₅₀, standard error (SE), and 95% confidence intervals (CI)for reference progestins from three individual studies EC50 95% CICompound Exp. (nM) SE lower upper Progesterone 1 0.616 0.026 0.509 0.7462 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637 Trimegestone 10.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.0094 3 0.00670.0003 0.0055 0.0082

[0353] TABLE 2 Estimated IC₅₀, standard error (SE), and 95% confidentinterval (CI) for the antiprogestin, RU486 from three individual studiesIC50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.0190.042 2 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

[0354] Progestational activity: Compounds that increase PRE-luciferaseactivity significantly (p<0.05) compared to vehicle control areconsidered active.

[0355] Antiprogestational activity: Compounds that decrease 3 nMprogesterone induced PRE-luciferase activity significantly (p<0.05)

[0356] EC₅₀: Concentration of a compound that gives half-maximalincrease PRE-luciferase activity (default-nM) with SE.

[0357] IC₅₀: Concentration of a compound that gives half-maximaldecrease in 3 nM progesterone induced PRE-luciferase activity(default-nM) with SE.

[0358] 3. T47D Cell Proliferation Assay

[0359] The objective of this assay is the determination ofprogestational and antiprogestational potency by using a cellproliferation assay in T47D cells. A compound's effect on DNA synthesisin T47D cells is measured. The materials and methods used in this assayare as follows.

[0360] a. Growth Medium:

[0361] DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 10% (v/v) fetalbovine serum (not heat-inactivated), 100 U/ml penicillin, 100 mg/mlstreptomycin, and 2 mM GlutaMax (GIBCO, BRL).

[0362] b. Treatment Medium:

[0363] Minimum Essential Medium (MEM) (#51200-038GIBCO, BRL) phenolred-free supplemented with 0.5% charcoal stripped fetal bovine serum,100 U/ml penicillin, 200 mg/ml streptomycin, and 2 mM GlutaMax (GIBCO,BRL).

[0364] c. Cell Culture

[0365] Stock T47 D cells are maintained in growth medium. For BrdUincorporation assay, cells are plated in 96-well plates (Falcon, BectonDickinson Labware) at 10,000 cells/well in growth medium. Afterovernight incubation, the medium is changed to treatment medium andcells are cultured for an additional 24 hr before treatment. Stockcompounds are dissolved in appropriate vehicle (100% ethanol or 50%ethanol/50% DMSO), subsequently diluted in treatment medium and added tothe cells. Progestin and antiprogestin reference compounds are run infull dose-response curves. The final concentration of vehicle is 0.1%.In control wells, cells receive vehicle only. Antiprogestins are testedin the presence of 0.03 nM trimegestone, the reference progestinagonist. Twenty-four hours after treatment, the medium is discarded andcells are labeled with 10 mM BrdU (Amersham Life Science, ArlingtonHeights, Ill.) in treatment medium for 4 hr.

[0366] d. Cell Proliferation Assay

[0367] At the end of BrdU labeling, the medium is removed and BrdUincorporation is measured using a cell proliferation ELISA kit (#RPN250, Amersham Life Science) according to manufacturer's instructions.Briefly, cells are fixed in an ethanol containing fixative for 30 min,followed by incubation in a blocking buffer for 30 min to reducebackground. Peroxidase-labeled anti-BrdU antibody is added to the wellsand incubated for 60 min. The cells are rinsed three times with PBS andincubated with 3,3′5,5′-tetramethylbenzidine (TMB) substrate for 10-20min depending upon the potency of tested compounds. Then 25 μl of 1 Msulfuric acid is added to each well to stop color reaction and opticaldensity is read in a plate reader at 450 nm within 5 min.

[0368] e. Analysis of Results:

[0369] Square root-transformed data are used for analysis of varianceand nonlinear dose response curve fitting for both agonist andantagonist modes. Huber weighting is used to downweight the effects ofoutliers. EC₅₀ or IC₅₀ values are calculated from the retransformedvalues. JMP software (SAS Institute, Inc.) is used for both one-wayanalysis of variance and non-linear dose response analyses in bothsingle dose and dose response studies.

[0370] f. Reference Compounds:

[0371] Trimegestone and medroxyprogesterone acetate (MPA) are referenceprogestins and RU486 is the reference antiprogestin. All referencecompounds are run in full dose-response curves and the EC₅₀ or IC₅₀values are calculated. TABLE 3 Estimated EC₅₀, standard error (SE), and95% confidence intervals (CI) for individual studies EC₅₀ 95% CICompound Exp (nM) SE lower upper Trimegestone 1 0.017 0.003 0.007 0.0402 0.014 0.001 0.011 0.017 3 0.019 0.001 0.016 0.024 MPA 1 0.019 0.0010.013 0.027 2 0.017 0.001 0.011 0.024

[0372] TABLE 4 Estimated IC₅₀, standard error, and 95% confidentinterval for the antiprogestin, RU486 IC₅₀ 95% CI Compound Exp (nM) SElower upper RU486 1 0.011 0.001 0.008 0.014 2 0.016 0.001 0.014 0.020 30.018 0.001 0.014 0.022

[0373] EC₅₀: Concentration of a compound that gives half-maximalincrease in BrdU incorporation with SE; IC₅₀: Concentration of acompound that gives half-maximal decrease in 0.1 trimegestone inducedBrdU incorporation with SE

[0374] 4. T47D Cell Alkaline Phosphatase Assay

[0375] The purpose of this assay is to identify progestins orantiprogestins by determining a compound's effect on alkalinephosphatase activity in T47D cells. The materials and methods used inthis assay are as follows.

[0376] a. Culture Medium:

[0377] DMEM:F12 (1:1) (GIBCO, BRL) supplemented with 5% (v/v) charcoalstripped fetal bovine serum (not heat-inactivated), 100 U/ml penicillin,100 μg/ml streptomycin, and 2 mM GlutaMax (GIBCO, BRL).

[0378] b. Alkaline Phosphatase Assay Buffer:

[0379] I. 0.1 M Tris-HCl, pH 9.8, containing 0.2% Triton X-100

[0380] II. 0.1 M Tris-HCl, pH 9.8 containing 4 mM p-nitrophenylphosphate (Sigma).

[0381] c. Cell Culture and Treatment:

[0382] Frozen T47D cells were thawed in a 37° C. water bath and dilutedto 280,000 cells/ml in culture medium. To each well in a 96-well plate(Falcon, Becton Dickinson Labware), 180 μl of diluted cell suspensionwas added. Twenty μl of reference or test compounds diluted in theculture medium was then added to each well. When testing for progestinantagonist activity, reference antiprogestins or test compounds wereadded in the presence of 1 nM progesterone. The cells were incubated at37° C. in a 5% CO₂/humidified atmosphere for 24 hr.

[0383] d. Alkaline Phosphatase Enzyme Assay:

[0384] At the end of treatment, the medium was removed from the plateand fifty μI of assay buffer I was added to each well. The plates wereshaken in a titer plate shaker for 15 min. Then 150 μl of assay bufferII was added to each well. Optical density measurements were taken at 5min intervals for 30 min at a test wavelength of 405 nM.

[0385] e. Analysis of Results: Analysis of Dose-Response Data

[0386] For reference and test compounds, a dose response curve isgenerated for dose (X-axis) vs. the rate of enzyme reaction (slope)(Y-axis). Square root-transformed data are used for analysis of varianceand nonlinear dose response curve fitting for both agonist andantagonist modes. Huber weighting is used to downweight the effects ofoutliers. EC₅₀ or IC₅₀ values are calculated from the retransformedvalues. JMP software (SAS Institute, Inc.) is used for both one-wayanalysis of variance and non-linear dose response analyses in bothsingle dose and dose response studies.

[0387] f. Reference Compounds:

[0388] Progesterone and trimegestone are reference progestins and RU486is the reference antiprogestin. All reference compounds are run in fulldose response curves and the EC₅₀ or IC₅₀ values are calculated. TABLE 5Estimated EC₅₀, standard error (SE), and 95% confidence intervals (CI)for reference progestins from three independent experiments EC50 95% CICompound Exp. (nM) SE lower upper Progesterone 1 0.839 0.030 0.706 0.9962 0.639 0.006 0.611 0.669 3 1.286 0.029 1.158 1.429 Trimegestone 1 0.0840.002 0.076 0.091 2 0.076 0.001 0.072 0.080 3 0.160 0.004 0.141 0.181

[0389] TABLE 6 Estimated IC₅₀, standard error, and 95% confidentinterval for the reference antiprogestin RU486 from three independentexperiments IC 50 95% CI Compound Exp (nM) SE lower upper RU486 1 0.1030.002 0.092 0.115 2 0.120 0.001 0.115 0.126 3 0.094 0.007 0.066 0.134

[0390] B. In-vivo Biology

[0391] The primary in-vivo assay is the rat decidualization model whichmay be used to determine progestational effects of both agonists andantagonists. The secondary in-vivo assay is the rat ovulation inhibitionmodel which is under development and hence the protocol is un-available.

[0392] 1. Rat Decidualization Assay

[0393] The objective of this procedure is used to evaluate the effect ofprogestins and antiprogestins on rat uterine decidualization and comparethe relative potencies of various test compounds. The materials andmethods used in tins assay are as follows.

[0394] a. Methods:

[0395] Test compounds are dissolved in 100% ethanol and mixed with cornoil (vehicle). Stock solutions of the test compounds in oil (Mazola™)are then prepared by heating (˜80° C.) the mixture to evaporate ethanol.Test compounds are subsequently diluted with 100% corn oil or 10%ethanol in corn oil prior to the treatment of animals. No difference indecidual response was found when these two vehicles were compared.

[0396] b. Animals (RACUC Protocol #5002)

[0397] Ovariectomized mature female Sprague-Dawley rats (˜60-day old and230 g) are obtained from Taconic (Taconic Farms, N.Y.) followingsurgery. Ovariectomy is performed at least 10 days prior to treatment toreduce circulating sex steroids. Animals are housed under 12 hrlight/dark cycle and given standard rat chow and water ad libitum.

[0398] c. Treatment

[0399] Rats are weighed and randomly assigned to groups of 4 or 5 beforetreatment. Test compounds in 0.2 ml vehicle are administered bysubcutaneous injection in the nape of the neck or by gavage using 0.5ml. The animals are treated once daily for seven days. For testingantiprogestins, animals are given the test compounds and a EC₅₀ dose ofprogesterone (5.6 mg/kg) during the first three days of treatment.Following decidual stimulation, animals continue to receive progesteroneuntil necropsy four days later.

[0400] d. Dosing

[0401] Doses are prepared based upon mg/kg mean group body weight. Inall studies, a control group receiving vehicle is included.Determination of dose-response curves is carried out using doses withhalf log increases (e.g. 0.1, 0.3, 1.0, 3.0 mg/kg . . . ).

[0402] e. Decidual Induction

[0403] Approximately 24 hr after the third injection, decidualization isinduced in one of the uterine horns by scratching the antimesometrialluminal epithelium with a blunt 21 G needle. The contralateral horn isnot scratched and serves as an unstimulated control. Approximately 24 hrfollowing the final treatment, rats are sacrificed by CO₂ asphyxiationand body weight measured. Uteri are removed and trimmed of fat.Decidualized (D-horn) and control (C-horn) uterine horns are weighedseparately.

[0404] f. Analysis of Results:

[0405] The increase in weight of the decidualized uterine horn iscalculated by D-horn/C-horn and logarithmic transformation is used tomaximize normality and homogeneity of variance. The Huber M-estimator isused to down weight the outlying transformed observations for bothdose-response curve fitting and one-way analysis of variance. JMPsoftware (SAS Institute, Inc.) is used for both one-way ANOVA andnon-linear dose-response analyses.

[0406] g. Reference Compounds:

[0407] All progestin reference compounds were run in full dose-responsecurves and the EC₅₀ for uterine wet weight were calculated. TABLE 7Estimated EC₅₀, standard error (SE), and 95% confidence intervals forindividual studies EC₅₀ 95% CI Compound Exp (mg/kg, s.c.) SE lower upperProgesterone 1 5.50 0.77 4.21 7.20 2 6.21 1.12 4.41 8.763-Ketodesogestrel 1 0.11 0.02 0.07 0.16 2 0.10 0.05 0.11 0.25 3 0.060.03 0.03 0.14 Levonorgestrel 1 0.08 0.03 0.04 0.16 2 0.12 0.02 0.090.17 3 0.09 0.02 0.06 0.13 4 0.09 0.02 0.06 0.14 MPA 1 0.42 0.03 0.290.60 2 0.39 0.05 0.22 0.67 3 0.39 0.04 0.25 0.61

[0408] TABLE 8 Estimated average EC₅₀, standard error, and 95%confidence intervals for dose-response curves of 3 reference compoundsEC50 95% CI Compound (mg/kg, s.c.) SE lower upper Progesterone 5.62 0.624.55 7.00 3-Ketodesogestrel 0.10 0.02 0.07 0.14 Levonorgestrel 0.10 0.010.08 0.12

[0409] TABLE 9 Estimated IC₅₀, standard error, and 95% confidentinterval for the antiprogestin, RU 486 IC₅₀ 95% CI Compound Exp. (mg/kg,p.o.) SE lower upper RU 486 1 0.21 0.07 0.05 0.96 2 0.14 0.02 0.08 0.27

[0410] Concentration: Compound concentration in assay(default-mg/kg bodyweight)

[0411] Route of administration: Route the compound is administered tothe animals

[0412] Body weight: Mean total animal body weight (default-kg)

[0413] D-horn: Wet weight of decidualized uterine horn (default-mg)

[0414] C-horn: Wet weight of control uterine horn (default-mg)

[0415] Decidual response: [(D-C)/C]×100%

[0416] Progestational activity: Compounds that induce decidualizationsignificantly (p<0.05) compared to vehicle control are considered active

[0417] Antiprogestational activity: Compounds that decrease EC₅₀progesterone induced decidualization significantly (p<0.05)

[0418] EC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal increase in decidual response (default-mg/kg)

[0419] IC₅₀ for uterine weight: Concentration of compound that giveshalf-maximal decrease in EC₅₀ progesterone induced decidual response(default-mg/kg) Data for Representative Compounds Decid. IC50 Example #Ki/nM CV-1 IC50/nM mg/kg 34 19 14 50% @ 10 35 22 19 50% @ 10 80 70% # 377 60% @ 3 44 123 20 50% @ 3 73 50% @ 3 36 4.8 9 50% @ 10 32 9 1 60% @10 47 18 7 50% @ 10

EXAMPLE 89

[0420]4-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-2-fluorobenzeneacetonitrile

[0421] Prepared from 4-bromo-2-fluorophenylacetonitrile and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronicacid according to the procedure for example 18 to afford the titlecompound as a white solid; mp. 180-183° C.; ¹H-NMR (DMSO-d₆) δ10.4 (s,1H), 7.7 (s, 1H), 7.6-7.7 (m. 4H) 6.9 (d, 1H, J=8.1 Hz), 4.1(s, 2H), 1.9(m, 2H), 1.7−1.6 (m, 8H). MS (APCI (−)) m/z 333 [M−H]⁻ Anal. calc. forC₂₁H₁₉FN₂O. 0.5 H₂O: C, 73.49, H, 5.87, N, 8.20. Found: C, 73.55, H,5.50, N, 7.36.

EXAMPLE 90

[0422]5-(3-Fluoro-4-methoxyphenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0423] Prepared from 4-bromo-2-fluoroanisole and(2′-oxo-2′,3′-dihydrospiro[cyclohexane-1,3′-[3H]indol]-5′-yl) boronicacid according to the procedure for example 18 to afford the titlecompound as a white solid, mp. 178-180° C.; ¹ H-NMR (DMSO-d₆) δ10.4 (s,1H), 7.65 (d, 1H, J=1.1 Hz), 7.5−7.4 (m, 3H), 7.2(t, 1H, J=8.9 Hz), 6.9(d, 1H, J=8 Hz), 3.9(s, 3H), 1.9 (m, 2H) 1.7−1.6 (m, 8H); MS (APCI (−))m/z 324 [M−H]⁻; Anal. Calc. For C₂₀H₂₀FNO₂. : C, 73.83, H, 6.20, N,4.30. Found: C, 73.55, H, 6.23, N, 4.40.

EXAMPLE 91

[0424] 5-(3-Chlorophenyl)spiro[cyclobutane-1,3-3H]indole]-2(1H)-one

[0425] 5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one. To a stirredsolution of spiro[cyclobutane-1,3′-[3H]indol]-2′(1′H)-one (J. Med. Chem.1987, 824-9) (1.0 g, 6 mmol) in glacial acetic acid (10 mL) was addeddropwise at room temperature a solution of bromine (0.30 mL, 6 mmol) inglacial acetic acid (6 mL). After stirring for 10 min, anhydrous sodiumacetate (0.47 g, 6 mmol) was added and the solution was concentrated invacuo. The residue was dissolved in ethyl ether (50 mL) and washedsequentially with water (50 mL), aqueous saturated sodium bicarbonatesolution (50 mL), water (50 mL) and brine (30 mL). The organic layer wasdried over magnesium sulfate, filtered and concentrated in vacuo.Crystallization from ethyl ether yielded the product as a white fluffysolid (1.1 g, 73%), mp 235-7° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ2.15-2.41(m, 6 H), 6.74 (d, 1 H, J=8.2 Hz), 7.33 (dd, 1 H, J=2, 8.2 Hz), 7.75 (d,1 H, J=2 Hz), 10.36 (bs, 1 H); MS (EI) m/z 251 [M⁺]; Anal. Calcd forC₁₁H₁₀BrNO: C, 52.41; H, 4.00; N, 5.56. Found: C, 51.98; H, 4.24; N,5.42.

[0426] To a solution of5-bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6 g, 2 mmol) inethylene glycol dimethyl ether (50 mL) under a nitrogen atmosphere wasadded tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). Tothe solution was added sequentially 3-chlorophenyl boronic acid (0.48 g,3 mmol) and potassium carbonate (0.76 g, 5 mmol) in water (5 mL). Themixture was heated to 80° C. for 3 h and allowed to cool. The reactionmixture was poured into water (100 mL) and extracted with ethyl acetate(3×100 mL). The organic layers were combined, washed with brine (50 mL)and dried over magnesium sulfate. The solution was filtered,concentrated in vacuo, and the residue was purified by HPLC (Zorbax PRO,C18, 10u, 15 A, 50×250 mm; 35% Water/65% AcCN; 254NM; AMB. temp.) togive the title compound (200 mg, 35%) as a white powder, mp 199.5-201°C. ¹H NMR (DMSO-d₆, 300 MHz) δ2.21-2.28 (m, 2 H), 2.40-2.45 (m, 4 H),6.87 (d, 1 H, J=8.1 Hz), 7.37 (‘d’, 1 H), 7.44-7.52 (m, 2 H), 7.65 (bd,1 H, J=7.8 Hz), 7.76 (bs, 1 H), 7.92 (bs, 1 H), 10.35 (s, 1 H). MS (EI)m/z 283 [M⁺]. Anal. Calcd for C₁₇H₁₄ClNO: C, 71.96; H, 4.97; N, 4.94.Found: C, 70.75; H, 5.07; N, 4.68.

EXAMPLE 92

[0427] 5-(3-Chlorophenyl)spiro[cyclopropane-1,3-1,3H]indole]-2(1H)-one

[0428] To 5-(3-chloro-phenyl)-1,3-dihydro-indol-2-one (1.2 g, 5 mmol) intetrahydrofuran (25 mL, anhydrous) at −20° C. was added slowlyn-butyllithium (2.5 M solution in hexanes, 3.93 mL, 9.8 mmol), followedby N,N,N′,N′-tetramethylethylenediamine (1.48 mL, 9.8 mmol). After 15min, 1,2-dibromoethane (1.27 mL, 15 mmol) was added slowly and themixture was allowed to reach room temperature. After 5 days, saturatedaqueous ammonium chloride solution (50 mL) and ethyl acetate (50 mL)were added. The layers were separated and the aqueous phase wasextracted with ethyl acetate (2×25 mL). The organic layers werecombined, washed with 1 N HCl (25 mL) and brine (25 mL), and dried overmagnesium sulfate. The solution was filtered and concentrated in vacuo.The residue was purified by flash column chromatography (40% ethylacetate/hexane) on a pad of silica gel to give the product (40 mg) aswhite crystals, mp 212-214° C.; ¹H NMR (CDCl₃, 300 MHz) δ1.59-1.63 (m, 2H), 1.80-1.84 (m, 2 H), 7.00-7.03 (m, 2 H), 7.28-7.42 (m, 4 H), 7.51(‘t’, 1 H), 7.85 (bs, 1 H). MS (EI) m/z 269 [M⁺]. Anal. Calcd forC₁₆H₁₂ClNO: C, 71.25; H, 4.48; N, 5.19. Found: C, 70.78; H, 4.88; N,5.10.

EXAMPLE 93

[0429]2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

[0430] 1-t-Butoxycarbonylpyrrole-2-boronic acid. To 1-tert-butylpyrrolecarboxylate (Aldrich, 25 g, 0.15 mol, 1.0 eq) in THF at −78° C.(anhydrous, 250 mL) was added LDA (2 M solution inheptane/THF/ethylbenzene, 82 mL, 1.1 eq). After stirring for 30 min at−78° C., trimethylborate (85 mL, 0.750 mol, 5.0 eq) was added. Afterstirring at −78° C. for 1 h, the dry ice bath was removed and thereaction was allowed to come to room temperature overnight. HCl (0.25 N,200 mL) was added to the reaction and the THF was removed in vacuo. Theaqueous layer was extracted with ethyl ether (3×300 mL). The combinedether layers were washed with water (2×200 mL), then with brine (200mL), and dried over magnesium sulfate. The solution was filtered andconcentrated in vacuo. When the product began to crystallize on therotary, the flask was removed and allowed to stand. The crystals werefiltered and washed with ice-cold ethyl ether to give the product (14 g,44%) as a white solid. Several crystallizations of filtrate from coldether gave more product (4.5 g, 14%).

[0431]5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester. To a solution of5-Bromospiro[cyclobutane-1,3-[3H]indol]-2(1H)-one (0.6 g, 2.4 mmol) inethylene glycol dimethyl ether (50 mL) under a nitrogen atmosphere wasadded tetrakis(triphenylphosphine)palladium(0) (140 mg, 0.1 mmol). Tothe solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronicacid (0.65 g, 3.1 mmol) and potassium carbonate (0.75 g, 5.4 mmol) inwater (5 mL). The mixture was heated to 80° C. for 3 h and allowed tocool. The reaction mixture was poured into water (100 mL) and extractedwith ethyl acetate (3×100 mL). The organic layers were combined, washedwith brine (50 mL) and dried over magnesium sulfate. The solution wasfiltered, concentrated in vacuo, and the residue was purified by flashcolumn chromatography to give the product (0.7 g, 86%) as a tan powder,mp 163-165° C. ¹H NMR (DMSO-d₆, 400 MHz) δ1.3 (s, 9 H), 2.16-2.49 (m, 6H), 6.19 (dd, 1 H, J=1.8, 3.2Hz), 6.24 (t, 1 H, J=3.3Hz), 6.76 (d, 1 H,J=8.1 Hz), 7.09 (dd, 1 H, J=1.8, 8.0 Hz), 7.30 (dd, 1 H, J=1.8, 3.3 Hz),7.48 (d, 1 H, J=1.8 Hz), 10.24 (s, 1 H). MS (APCI) m/z 339 [M+H]⁺. Anal.Calcd for C₂₀H₂₂N₂O₃: C, 70.99; H, 6.55; N, 8.28. Found: C, 69.51; H,6.38; N, 7.69.

[0432] To a solution of5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (0.97 g, 2.9 mmol) in acetonitrile (50 mL) anddichloromethane (5 mL) at −20° C. was added silver nitrate (0.51 g, 3.0mmol). After 20 min, acetyl chloride (0.20 mL, 2.9 mmol) in acetonitrile(3 mL) was added and the solution was allowed to come to roomtemperature. After 24 h, the reaction mixture was diluted withdichloromethane (100 mL) and filtered through celite. The filtrate waspoured into water (100 mL) and the layers were separated. The organiclayer was washed with brine (50 mL) and dried over magnesium sulfate.The solution was filtered, concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (40% ethylacetate/hexane) to give the title compound (415 mg, 37%) as a yellowpowder, mp 265° C. (dec.). ¹H NMR (DMSO-d₆; 400 MHz) δ1.45 (s, 9 H),2.17-2.48 (m, 6 H), 6.60 (d, 1 H, J=4.2 Hz), 6.90 (d, 1 H, J=8.1 Hz),7.35 (dd, 1 H, J=2.0, 8.1 Hz), 7.46 (d, 1 H, J=4.2 Hz), 7.70 (‘d’, 1 H,J=1.8 Hz), 10.50 (s, 1 H). MS (ESI) m/z 382 [M−H]¹. Anal. Calcd forC₂₀H₂₁N₃O₅: C, 62.65; H, 5.52; N, 10.96. Found: C, 62.58; H, 5.60; N,10.91.

EXAMPLE 94

[0433]2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

[0434] To a solution of5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (1.5 g, 4.0 mmol) in acetonitrile (50 mL) anddichloromethane (5 mL) at −20° C. was added silver nitrate (0.76 g, 4.5mmol). After 20 min, acetyl chloride (0.30 mL, 4.0 mmol) in acetonitrile(3 mL) was added and the solution was allowed to come to roomtemperature. After 24 h, the reaction mixture was diluted withdichloromethane (100 mL) and filtered through celite. The filtrate waspoured into water (100 mL) and the layers were separated. The organiclayer was washed with brine (50 mL) and dried over magnesium sulfate.The solution was filtered, concentrated in vacuo and the residue waspurified by flash column chromatography on silica gel (40% ethylacetate/hexane) to give the title compound (650 mg, 41%) as a yellowpowder, mp 150-153° C. ¹H NMR (DMSO-d₆; 400 MHz) δ1.42 (s, 9 H),1.77-2.00 (m, 8 H), 6.55 (d, 1 H, J=4.2 Hz), 6.93 (d, 1 H, J=8.0 Hz),7.33 (dd, 1 H, J=1.7, 8.0 Hz), 7.37 (‘d’, 1 H, J=1.7 Hz), 7.43 (d, 1 H,J=4.2 Hz), 10.53 (s, 1 H). MS ((−) APCI) m/z 396 [M−H]⁻. Anal. Calcd forC₂₁H₂₃N₃O₅: C, 63.47; H, 5.83; N, 10.57. Found: C, 62.95; H, 5.52; N,10.32.

EXAMPLE 95

[0435]5-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclobutane-1,3-[3H]indol]-2(1H)-one

[0436]2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclobutane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (350 mg, 0.91 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 150°C. After 20 min at this temperature, the flask was removed from the oilbath and allowed to cool. The residue was dissolved in acetone and waspurified by flash column chromatography (40% ethyl acetate/hexane) on apad of silica gel. Further purification by HPLC gave the title compound(100 mg, 39%) as a bright yellow powder, mp 250° C. (dec.); ¹H NMR(DMSO-d₆, 400 MHz) δ2.18-2.48 (m, 6 H), 6.77 (dd, 1 H, J=2.4, 4.4 Hz),6.83 (d, 1 H, J=8.1 Hz), 7.25 (dd, 1 H, J=2.4, 4.3 Hz), 7.73 (dd, 1 H,J=2.0, 8.1 Hz), 8.23 (‘d’, 1 H, J=1.8 Hz), 10.41 (bs, 1 H), 13.13 (s, 1H); MS (ESI) m/z 282 [M−H]. Anal. Calcd. For C₁₅H₁₃N₃O₃: C, 63.60; H,4.63; N, 14.83. Found: C, 62.59; H, 4.58; N, 14.28.

EXAMPLE 96

[0437]5-(5-Nitro-1H-pyrrol-2-yl)spiro[cyclopentane-1,3-[3H]indol]-2(1H)-one

[0438]2-Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (580 mg, 1.5 mmol) was placed in a 25 mL roundbottomed flask stoppered with a rubber septum and equipped with nitrogeninlet and a needle to allow gaseous outflow. A vigorous flow of nitrogenwas maintained as the flask was placed in an oil bath and heated to 150°C. After 20 min at this temperature, the flask was removed from the oilbath and allowed to cool. The residue was dissolved in acetone and waspurified by flash column chromatography (40% ethyl acetate/hexane) on apad of silica gel. Further purification by HPLC gave the title compound(300 mg, 67%) as a yellow powder, mp 275° C. (dec.). ¹H NMR (DMSO-d₆,400 MHz) δ1.78-2.07 (m, 8 H), 6.77 (dd, 1 H, J=2.4, 4.2Hz), 6.86 (d, 1H, J=8.2 Hz), 7.24 (dd, 1 H, J=2.4, 4.2 Hz), 7.71 (dd, 1 H, J=1.8, 8.2Hz), 7.87 (‘d’, 1 H, J=1.8 Hz), 10.47 (bs, 1 H), 13.12 (s, 1 H). MS(ESI) m/z 296 [M−H]⁻. Anal. Calcd. For C₁₆H₁₅N₃O₃: C, 64.64; H, 5.09; N,14.13. Found: C, 63.82; H, 5.20; N, 13.73.

EXAMPLE 97

[0439]5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester

[0440] A solution of5′-Bromospiro[cyclopentane-1,3′-[3H]indol]-2′(1H)-one (2.0 g, 7.5 mmol)and tetrakis(triphenylphosphine)palladium(0) (430 mg, 0.3 mmol) inethylene glycol dimethyl ether (50 mL) was stirred under a flow ofnitrogen for 15 min. To the solution was added sequentially1-t-butoxycarbonylpyrrole-2-boronic acid (2.1 g, 9.7 mmol) and potassiumcarbonate (2.4 g, 17 mmol) in water (10 mL). The mixture was heated to80° C. for 3 h and allowed to cool. The reaction mixture was poured intowater (50 mL) and extracted with ethyl acetate (3×50 mL). The organiclayers were combined, washed with brine (30 mL) and dried over magnesiumsulfate. The solution was filtered and concentrated in vacuo.Crystallization from 20% ethyl acetate/hexane gave the product (2.2 g,83%) as a white powder, mp 179-180.5° C. ¹H NMR (DMSO-d₆, 400 MHz) δ1.30(s, 9H), 1.75-1.98 (m, 8 H), 6.16 (dd, 1 H, J=1.8, 3.3 Hz), 6.22 (‘t’, 1H, J=3.3, 3.3 Hz), 6.79 (d, 1 H, J=7.9 Hz), 7.08 (dd, 1 H, J=1.8, 7.9Hz), 7.14 (‘d’, 1 H, J=1.5 Hz), 7.28 (dd, J=1.9, 3.3 Hz), 10.30 (s, 1H); MS (EI) m/z 352 [M⁺]; Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.57; H, 6.86;N, 7.95. Found: C, 71.08; H, 6.83; N, 7.74.

[0441] To a solution of5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylicacid, tert-butyl ester (2.2 g, 6.0 mmol) in THF (anhydrous, 25 mL) wasadded at −78° C. chlorosulfonyl isocyanate (0.63 mL, 7.0 mmol). After 90min, dimethylformamide (11 mL, 140 mmol) was added and the reaction wasallowed to warm to room temperature. The reaction mixture was pouredinto water (50 mL) and extracted with ethyl acetate (2×50 mL). Theorganic layers were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash column chromatography on silica gel (30% ethyl acetate/hexane)gave the title compound (1.7 g, 75%) as white crystals, mp 167-9° C.; ¹HNMR (DMSO-d₆, 400 MHz) δ1.34 (s, 9H), 1.75-1.98 (m, 8 H), 6.39 (d, 1 H,J=3.7 Hz), 6.84 (d, 1 H, J=7.9 Hz), 7.17 (dd, 1 H, J=1.8, 7.9 Hz), 7.28(‘t’, 2 H), 10.41 (s, 1 H); MS (ESI) m/z 376 [M−H]⁻. Anal. Calcd. forC₂₂H₂₃N₃O₃: C, 70.01; H, 6.14; N, 11.13. Found: C, 69.67; H, 6.38; N,11.04.

EXAMPLE 98

[0442]5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-4-propyl-2-thiophenecarbonitrile

[0443] The title compound was prepared in a manner similar to example 69from 5-bromo-4-n-propyl thiophene-2-carbonitrile (1.17 g, 5 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol])-5-boronic acid (1.24g, 5 mmol), tetrakis(triphenylphosphine) palladium, potassium carbonate(2.75 g, 21 mmol), water (10 mL), and dimethoxyethane (50 mL) heated atreflux over night, to afford the title compound (0.7 g, 40%): m.p.168-171° C.; ¹H NMR (DMSO-d₆) 6 10.56 (s, 1H), 7.93 (s, 1H) 7.52−7.51(d, 1H, J=1.5 Hz), 7.33−7.29 (dd, 1H, J=1.6 Hz), 7.00−6.96 (d, 1H, J=8.0Hz), 2.62−2.57 (t, 2H), 1.86 (m, 2H), 1.70−1.56 (m, 11 H), 0.88−0.84 (t,H); MS m/z (APCI (+)) 351 [M+H]⁺. IR (KBr) 1620, 1700, 2200 cm⁻¹; Anal.Calc. For C₂₁H₂₂N₂OS {fraction (1/2 )} H₂O: C, 70.2; H, 6.39; N, 7.79.Found. C, 70.67; H,6.34; N,7.62.

EXAMPLE 99

[0444]5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)4-n-butyl-2-thiophenecarbonitrile

[0445] The title compound was prepared in a manner similar to example 69from 5-bromo-4-n-butyl thiophenecarbonitrile¹ (1.24 g, 5.1 mmol),(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol])-5-boronic acid (1.24g, 5.05 mmol), tetrakis(triphenylphosphine) palladium (0.25 g),potassium carbonate (2.75 g, 21 mmol), water (10 mL),and dimethoxyethane(50 mL) heated at reflux for 5 hours to afford the title compound (1 g,54%), m.p.130-132° C. ¹H NMR (DMSO-d₆) δ10.56 (s, 1H), 7.92 (s, 1H),7.52−7.51 (d, 1H, J=1.2 Hz), 7.32−7.29 (dd, 1H, J=1.5 Hz), 6.98−6.96 (d,1H, J=8.0 Hz), 2.64−2.59 (t, 2H), 1.99−1.86 (m, 2H), 1.70−1.5 (m, 11 H),1.32−1.22 (m, 2H), 0.86−0.82 (t, 3H); MS (APCI (+)) m/z 365 [M+H]⁺; IR(KBr) 1620,1700;2200 cm⁻¹; Anal. Calc. For C₂₂H₂₄N₂OS ¼ H₂O. C, 71.61;H, 6.69; N, 7.59. Found: C, 71.13; H, 6.61; N, 6.91.

EXAMPLE 100

[0446]5-(3-Chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0447] To a −25° C. solution of 4-methyl-2-oxindole (3.0 g, 20.2 mmol)(Tett, 1966, 22, 10, 3337-43) in anhydrous THF (100 mL) under N₂ isadded N,N,N′,N′-tetramethylethylenediamine (8.0 mL, 51.0 mmol) followedby dropwise addition of n-butyl lithium (10.0 M in hexanes, 5.1 mL, 51.0mmol). After 30 min. a solution of 1,5-diiopentane (9.2 mL, 61.0 mmol)in 3 (mL) of THF was added and the reaction mixture was allowed to warmto RT and stir for 14 h. The reaction mixture was poured into water,extracted with EtOAc (×2), the combined organic layers were washed withdil. HCl (pH 1), water (×2), dried (MgSO₄) and evaporated. The residuewas purified by column chromatography (SiO₂, ethyl acetate: hexane 1:4)to afford the product (3.2 g, 15 mmol, 74%) as a tan solid: ¹H NMR(CDCl₃) δ1.2-1.45 (m, 1H), 1.55-1.75 (m, 4H), 1.85-1.95 (d, J=13 Hz,1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H), 6.72 (dd, J=8.1, 1.0 Hz, 1H), 6.95(dd, J=8.1, 8.0 Hz, 1H), 7.32 (dd, J=8.0, 1.0 Hz, 1H), 8.6 (br s, 1H).

[0448] 5-Bromo-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one. Asolution of the above oxindole (0.44 g, 2.0 mmol) in CHCl₃ (10 mL) withsodium acetate (0.28 g, 3.4 mmol) is cooled to 0° C. and treated withbromine (0.11 mL, 2.0 mmol) in CHCl₃ (4 mL). After 30 min. the mixtureis warmed to RT and stirred an additional hour. The reaction mixture ispoured into sat. sodium hydrogen carbonate solution and extracted withEtOAc (×2), the combined organic layers were washed with water, sat.sodium hydrogen carbonate solution, water, dried (MgSO₄), and evaporatedto give an off-white solid which was purified by column chromatography(SiO₂, ethyl acetate: hexane 2:4) to afford (0.2 g, 0.7 mmol, 35%) oftheproduct: ¹H NMR (CDCl₃) δ1.2-1.45 (m, 1H), 1.55-1.75 (m, 4H), 1.85-1.95(d, J=13 Hz, 1H), 2.05-2.35 (m, 4H), 2.47 (s, 3H), 6.62 (d, J=8.0 Hz,1H), 7.4 (d, J=8.0 Hz, 1H), 8.47 (br s, 1H).

[0449]5-(3-chlorophenyl)-4-methylspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one. Asolution of the above 5-bromo-4-methyl-oxindole (0.1 g, 0.34 mmol) andtetrakis(triphenylphosphine) palladium (0.05 g, 0.04 mmol) indimethoxyethane (10 mL) was stirred under N₂ for 20 min. To this mixturewas then added 3-chlorophenylboronic acid (0.065 g, 0.41 mmol) andsodium carbonate (0.1 g, 1.0 mmol) in water (3 mL). The solution wasbrought to reflux for 6 h then cooled to RT, poured into water andextracted with EtOAc (×3). The combined organic extracts were washedwith water, brine, dried (MgSO₄), and evaporated. The residue waspurified by column chromatography (SiO₂, ethyl acetate: hexane 1:3) toafford the subtitled compound (0.077 g, 0.2 mmol, 70%) as ayellow solid:mp. 164-165° C.; ¹H NMR (CDCl₃) δ1.25-1.4 (m 1H), 1.6-1.7 (m, 3H), 1.78(d, J=12.0 Hz, 2H), 1.9 (d, J=13.0 Hz, 1H), 2.1-2.35 (m, 3H), 2.49 (s,3H), 6.75 (d, J=7.9 Hz, 1H), 7.1 (d, J=7.9 Hz, 1H), 7.15-7.18 (m, 1H),7.26-7.35 (m, 3H), 7.88 (br s, 1H); ¹³C-NMR (CDCl₃) δ16.71 (q), 20.7,25.5, 29.9 (t), 48.5 (s), 107.1, 127.0, 128.0, 129.4, 129.5, 130 (d),132.2, 133.0, 134.0, 136.6, 140.1, 144, 182.6 (s); MS (EI) m/z 326,(M+H)+w/1 Cl.

EXAMPLE 101

[0450]5-(1,2-Dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile

[0451] To a solution of tert-butyl2-cyano-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate(0.11 g, 2.6 mmol) in TFA (5 mL) at 0° C. was added silver nitrate (1.1eq, 49 mg, 2.86 mmol). After 5 min the reaction was poured onto ice, DCM(5 mL) was added and the layers were separated. The aqueous layer wasextracted with DCM (3×5 mL) and the combined organic layer was washedwith brine, dried over MgSO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel eluting with 40%ethyl acetate/hexane to5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)-1H-3-nitropyrrole-2-carbonitrile(20 mg, 21%) as a white solid. ¹H NMR (400 MHz, d₆-DMSO) δ1.4-1.9 (10H,m), 6.94 (d, 1H, J=8.1 Hz), 7.47 (dd, 1H, J=8.1, 1.75 Hz), 7.73 (s, 1H),7.75 (d, 1H, J=1.75 Hz), 10.6 (s, 1H), 13.4 (s, 1H). M/z (ES) 335(M−H)⁻. Anal. calcd for C₁₈H₁₆N₄O₃, C, 64.3, H, 4.79, N, 16.7. Found, C,62.2, H, 5.20, N, 15.1.

EXAMPLE 102

[0452]5-(2-Nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one.

[0453] According to a procedure described in J. Med. Chem. 1983, 26,p.800, succinic anhydride (2.0 g, 20 mmol) andspiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (4.03 g, 20 mmol) gave4-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoicacid (100%). ¹H NMR (d₆-DMSO, 300 MHz) δ1.5-2.0 (m, 10H), 2.56 (t, 1H,J=6 Hz), 3.20 (t, 1H, J=6 Hz), 6.95 (d, 1H, J=8.1 Hz), 7.91 (d, 1H,J=8.1 Hz), 8.0 (s, 1H), 10.7 (s, 1H), 12.1 (s, 1H). MS (EI) m/z 300(M−H)⁻.

[0454] According to a procedure described in J. Org. Chem. 1984, p.38404-oxo-4-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butanoicacid (5.64 g, 18 mmol) and thallium nitrate gavedimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate(7.95 g, 18 mmol) as a white powder (71%). ¹H NMR (d₆-DMSO, 300 MHz)δ1.44-1.84 (m, 1H), 2.68 (dd, 1H, J=4.97, 16.9 Hz), 3.06 (dd, 1H,J=16.9, 10.5 Hz), 3.5 (s, 6H), 4.03 (dd, 1H, J=4.9, 10.5 Hz), 6.78 (d,1H, J=7.9 Hz), 7.07 (d, 1H, J=7.9 Hz), 7.39 (s, 1H), 10.31 (s, 1H). MS(EI) m/z 346 (M+H)⁺.

[0455] To a solution ofdimethyl-2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)succinate(2.0g, 6.0 mmol) in THF (30 mL) was added LiBH₄ (2.5 eq, 0.33 g, 15mmol). The solution was refluxed for 1.5 h, cooled and quenched by thecareful addition of 1N HCl. The aqueous layer was extracted with DCM(3×10 mL) and the combined organic layer was washed with brine, driedover MgSO₄ and purified by flash column chromatography on silica geleluting with 5% MeOH/ethyl acetate to give of2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol(78 g, 47%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ1.53-1.60 (m,1H), 1.72 (m, 2H), 1.93 (m, 7H), 2.69 (m, 1H), 3.26 (m, 2H), 3.46 (t,2H, J=5.8 Hz), 4.35 (t, 1H, J=5.2 Hz), 4.55 (t, 1H, J=5.2 Hz), 6.70 (d,1H, J=7.8 Hz), 6.94 (d, 1H, J=7.8 Hz), 7.03 (s, 1H), 10.2 (s, 1H). M/z(ES) 276 (M+H⁺. Anal. calcd for C₁₆H₂₁NO₃, C, 96.79, H, 7.69, N, 5.09.Found, C, 70.02, H, 7.64, N, 5.02.

[0456] Oxalyl chloride (4 eq, 1.0 mL, 11 mmol) in DCM (40 mL) at −78° C.was treated with DMSO (8 eq, 1.62 mL, 22 mmol). After 2 min a solutionof2-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol]-5-yl)butan-1,4-diol(1 eq, 0.78 g, 2.9 mmol) in DMSO:DCM (1:3, 5 mL) was added followed 15min later by addition of triethylamine (18 eq, 7.2 mL, 52 mmol). Thesolution was removed from the cooling bath and allowed to reach roomtemperature. The solution was filtered through celite, concentrated invacuo and redissolved in MeOH (10 mL). A large excess of ammoniumacetate was added and the solution was heated to 60° C. for 1 h thenstored in a refrigerator for 16 h. The solution was partitioned betweenDCM and water. The layers were separated and the aqueous layer wasextracted with DCM (3×10 mL) and the combined organic layer was washedwith brine, dried over MgSO₄ and purified by flash column chromatographyon silica gel eluting with 60% ethyl acetate/hexane to give5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (0.12 g,19%) as a white solid. ¹H NMR (300 MHz, d₆-DMSO) δ1.79-1.83 (m, 2H),1.95 (in, 6H), 6.37 (s, 1H), 6.73 (m, 2H), 7.13 (s, 1H), 7.29 (d, 1H,J=8 Hz), 10.17 (s, 1H), 10.83 (s, 1H). M/z (ES) 253 (M+H)⁺.

[0457] To a solution of5-(1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (45 mg,0.17 mmol) in DCM:MeCN (1:1, 5 mL) at −40° C. sequentially was addedsilver nitrate (1.1 eq, 32 mg, 0.19 mmol) and a solution of acetylchloride (1.1 eq, 0.01 mL, 0.19 mmol) in MeCN (0.5 mL). After 1 h thecooling bath was removed and the reaction was allowed to stir for 16 h.DCM (20 mL) was added and the suspension was filtered through celite,washed sequentially with sat. aq. NaHCO₃ and brine, dried over MgSO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with 40% ethyl acetate/hexane togive5-(2-nitro-1H-pyrrol-3-yl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one (20mg, 40%) as a yellow powder. ¹H NMR (300 MHz, d₆-DMSO) δ1.63-1.95 (m,10J), 6.44 (t, 1H, J=2.69 Hz), 6.97 (d, 1H, J=8.1 Hz), 7.22 (t, 1H,J=2.9 Hz), 7.44 (dd, 1H, J=8.1, 1.7 Hz), 7.79 (d, 1H, J=1.4 Hz), 9.39(s, 1H), 11.85 (s, 1H). M/z 310 (M−H)⁻.

EXAMPLE 103

[0458] 5-(4-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0459] The title compound was prepared from CAT-817819 (1.9 g, 7.8 mmol)and 4-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method forExample 18 to afford the product (0.68 g, 42%) as an off white solid:mp. 226-229° C.; ¹ H NMR (DMSO-d₆) δ10.41 (br s, 1H), 7.68−7.63 (m, 3H),7.49−7.46 (m, 3H), 6.93 (d, 1H, J=8.0 Hz), 1.99−1.82 (m, 2H), 1.76−1.51(m, 8H); MS (EI) m/z 311/313 [M]⁺; C₁₉H₁₈ClON requires C, 73.19; H,5.82; N, 4.49; Found C, 73.13; H, 5.68; N, 4.40.

EXAMPLE 104

[0460] 5-(2-Chlorophenyl)spiro[cyclohexane-1,3-[3H]indol]-2(1H)-one

[0461] The title compound was prepared from CAT-817819 (1.9 g, 7.8 mmol)and 2-bromochlorobenzene (1.0 g, 5.2 mmol) according to the method forExample 18 to afford the title compound (0.68 g, 42%) as an off whitesolid: mp. 174-175° C; ¹H NMR (DMSO-d₆) δ10.43 (br s, 1H), 7.56−7.52 (m,2H), 7.43→7.33 (m, 3H), 7.25 (dd, 1H, J=8.0 and 1.7 Hz), 6.93 (d, 1H,J=8.0 Hz), 1.92−1.79 (m, 2H) and 1.77−1.43 (M, 8H); MS (EI) m/z 311/313[M]⁺; Anal. Calc. For C₁₉H₁₈ClON: C, 73.19; H, 5.82; N, 4.49; Found C,73.10; H, 5.86; N, 4.30.

EXAMPLE 105

[0462]5-(1,2-Dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-2-furancarbonitrile

[0463] The title compound was prepared from CAT-830083 (0.9 g, 3.9 mmol)and 5-cyano-furancarbonitrile (0.5 g, 2.6 mmol) according to the methodfor Example 18 to afford the title compound (0.35, 49%) as an off whitesolid: mp. 193-194° C; ¹H NMR (DMSO-d₆) δ10.55 (br s, 1H), 7.69−7.63 (m,3H), 7.15 (d, 1H, J=3.8 Hz), 6.92 (d, 1H, J=8.1 Hz), 2.00−1.83 (m, 8H);MS (ESI (−)) m/z 277 [M−H]⁻. Anal. Calc. For C₁₇H₁₄N₂O₂: C, 73.73; H,5.07; N, 10.07; Found C, 73.01; H, 4.98; N. 9.69.

[0464] All publications cited in this specification are incorporatedherein by reference herein. While the invention has been described withreference to a particularly preferred embodiment, it will be appreciatedthat modifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

What is claimed:
 1. A compound of the Formula 1:

wherein: R₁ and R₂ are selected from the group consisting of H, alkyl,substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; R₃ is selected from thegroup consisting of H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, and_COR^(A);R^(A) is selected from the group consisting of H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl; R₄ isselected from the group consisting of H, halogen, CN, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ isselected from the group consisting of a), b) c), and d): a) asubstituted benzene ring containing the substituents X, Y and Z as shownbelow:

wherein: X is selected from the group consisting of halogen, OH, CN, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁to C₃ alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl,S(O)alkyl, S(O)₂alkyl, C₁ to C₃ aminoalkyl, substituted C₁ to C₃aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6 membered heterocyclicring containing in its backbone 1 to 3 heteroatoms, COR^(B), OCOR^(B),and NR^(C)COR^(B); R^(B) is H, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(C)is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; Y and Z areindependently selected from the group consisting of H, halogen, CN, NO₂,C₁ to C₃ alkoxy, C₁ to C₃ alkyl, and C₁ to C₃ thioalkyl; b) a fivemembered heterocyclic ring having in its backbone 1, 2, or 3 heteroatomsselected from the group consisting of O, S, SO, SO₂ and NR⁶ andcontaining one or two independent substituents selected from the groupconsisting of H, halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁to C₃ aminoalkyl, COR^(D), and NR^(E)COR^(D); with the proviso that whenthe five-membered heterocyclic ring having in its backbone one NR⁶heteroatom is attached at the 2-position on said ring, the CNsubstituent is attached at the 1-, 3-, 4-, or 5-position of said ring;c) a six membered heterocyclic ring having in its backbone 1 or 2heteroatoms selected from the group consisting of O, S, SO, SO₂ and NR⁶and containing one or two independent substituents selected from thegroup consisting of H, halogen, CN, NO₂, C₁ to C₃ alkyl, C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, COR^(D), and NR^(E)COR^(D); R^(D) is H, C₁to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ toC₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; R⁶ is H or C₁ to C₃ alkyl; and d) anindol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety beingoptionally substituted by from 1 to 3 substituents selected from thegroup consisting of halogen, lower alkyl, CN, NO₂, lower alkoxy, andCF₃; or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein R⁵ is a disubstituted benzene ringcontaining the substituents X and Y as shown below:

wherein: X is selected from the group consisting of halogen, CN, C₁ toC₃ alkoxy, C₁ to C₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 memberedheterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C₁to C₃ thioalkoxy; and Y is on the 4′ or 5′ position of the disubstitutedbenzene ring and is selected from the group consisting of H, halogen,CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, and C₁ to C₃ thioalkyl; or apharmaceutically acceptable salt thereof.
 3. The compound according toclaim 1, wherein R⁵ is a five membered ring with the structure:

wherein: U is O, S, or NR⁶, R⁶ is H, C₁ to C₃ alkyl, C₁ to C₄ CO₂alkyl,X′ is selected from the group consisting of halogen, CN, NO₂, C₁ to C₃alkyl and C₁ to C₃ alkoxy; with the proviso that when X′ is CN, U is notNR⁶; Y′ is selected from the group consisting of H, F, CN, NO₂, and C₁to C₄ alkyl; or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 1, wherein R⁵ is a six membered ring withthe structure shown below:

wherein: X¹ is CX²; X² is halogen, CN or NO₂; or pharmaceuticallyacceptable salt thereof.
 4. The compound according to claim 1, which isselected from the group consisting of: i)5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one; ii)3-methyl-5-(3-nitrophenyl)-1,3-dihydro-indol-2-one; iii)5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one; iv)5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one; v)3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one; vi)5-(3-Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one; vii)5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one; viii)5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one; ix)5-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one; andx) 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one; or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1, which isselected from the group consisting of: i)5-(3-Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one; ii)3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile; iii)5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methylthiophene-2-carbonitrile; iv)5-(3-Chloro-5-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one; v)5-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one; vi)4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;vii)5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;viii)3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-5-fluoro-benzonitrile;ix) 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole; x)5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene-2-carbonitrile;xi)3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile;and xii)3,3-Dimethyl-5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one; or apharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier orexcipient.
 7. A method of inducing contraception in a mammal, the methodcomprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 8. A method of treating or preventing benign ormalignant neoplastic disease, the method comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof.
 9. The methodof claim 8, wherein the benign or malignant neoplastic disease isselected from the group consisting of uterine myometrial fibroids,endometriosis, benign prostatic hypertrophy; carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate,pituitary, meningioma and other hormone-dependent tumors.
 10. A compoundof the Formula 1:

wherein: R₁ and R₂ are selected from the group consisting of H, alkyl,substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl,substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl,alkylheteroaryl, 1-propynyl, and 3-propynyl; R₃ is selected from thegroup consisting of H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆alkyl, C₃ to C₆ alkenyl, alkynyl, substituted alkynyl, and COR^(A);R^(A) is selected from the group consisting of H, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ aminoalkyl, and substituted C₁ to C₃ aminoalkyl; R₄ isselected from the group consisting of H, halogen, CN, NH₂, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl C₁ to C₆ alkoxy, substituted C₁ to C₆alkoxy, C₁ to C₆ aminoalkyl, and substituted C₁ to C₆ aminoalkyl; R⁵ isa six membered ring with the structure shown below:

wherein: X¹ is N; X² is halogen, CN or NO₂; or pharmaceuticallyacceptable salt thereof.
 11. A pharmaceutical composition comprising acompound of claim 10, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier or excipient.
 12. A method ofinducing contraception in a mammal, the method comprising administeringto a mammal in need thereof a pharmaceutically effective amount of acompound of claim 10, or a pharmaceutically acceptable salt thereof. 13.A method of treating or preventing benign or malignant neoplasticdisease, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound of claim 10, or apharmaceutically acceptable salt thereof.
 14. The method of claim 12,wherein the benign or malignant neoplastic disease is selected from thegroup consisting of uterine myometrial fibroids, endometriosis, benignprostatic hypertrophy; carcinomas and adenocarcinomas of theendometrium, ovary, breast, colon, prostate, pituitary, meningioma andother hormone-dependent tumors.
 15. A method of hormone replacementtherapy, the method comprising administering to a mammal in need thereofa pharmaceutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.
 16. A method of hormonereplacement therapy, the method comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound of claim10, or a pharmaceutically acceptable salt thereof.